Nitrogen-containing heterocyclic compounds, their production and use

ABSTRACT

A compound of the formula:  
                 
 
     wherein one of A and D is N and the other is C, or both are N; B is N or C; m is 0-3; R 1 , R 2  and R 3  each is (i) H or (ii) a group bound via C, N, O or S; R 4  is a group bound via C; R 5  is H or a group bound via C or O; R 6  is H or a group bound via C; R 7  is a homo- or hetero-cyclic group which may be substituted; or a salt thereof possesses excellent gonadotropin-releasing hormone antagonizing activity, and is useful as a prophylactic or therapeutic agent for sex hormone-dependent diseases, and so forth.

TECHNICAL FIELD

[0001] The present invention relates to nitrogen-containing heterocycliccompounds exhibiting gonadotropin releasing hormone (GnRH) antagonizingactivity, their production and pharmaceutical compositions containingthem.

BACKGROUND ART

[0002] The secretion of hypophysial anterior lobe hormone is regulatedby the peripheral hormone secreted by each target organ and thesecretion-promoting or secretion-suppressing hormone secreted by thehypothalamus, which is the center superior to the hypophysial anteriorlobe, and this group of hormones hereinafter generically referred to ashypothalamic hormone in this specification. To date, nine hypothalamichormones have been identified, for example, thyroid-stimulatinghormone-releasing hormone (TRH), and gonadotropin releasing hormone[GnRH, also known as luteinizing hormone releasing hormone (LH-RH)],etc. It is conjectured that these hypothalamic hormones exhibit theirhormone actions etc. via receptors assumed to be present in thehypophysial anterior lobe, and analyses of receptor genes specific tothese hormones, including humans, are ongoing. Antagonists or agoniststhat act specifically and selectively on these receptors would thereforeregulate the action of hypothalamic hormones and hence regulate thesecretion of hypophysial anterior lobe hormone. As a result, suchantagonists or agonists are expected to prevent or treat diseasesdepending on these hypophysial anterior lobe hormone.

[0003] Known compounds possessing GnRH-antagonizing activity includeGnRH-derived linear peptides (U.S. Pat. Nos. 5,140,009 and 5,171,835), acyclic hexapeptide derivative (JP-A-61-191698), a bicyclic peptidederivative [Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273(1993)), and so forth. Non-peptide compounds possessingGnRH-antagonizing activity include compounds described in WO 95/28405,WO 97/14697 and WO 97/14682, etc.

[0004] ZA 86/9289 describes1,4-dihydro-1-ethyl-7-phenylpyrrolo[1,2-a]pyrimidin-4-one in Example 22.

[0005] Peptide compounds pose a large number of problems to be resolvedwith respect to oral absorbability, dosage form, dose volume, drugstability, sustained action, metabolic stability etc. There is strongdemand for an oral GnRH antagonist, especially one based on anon-peptide compound, that has excellent therapeutic effect onhormone-dependent cancers, e.g., prostatic cancer, endometriosis,precocious puberty etc., and that does not show transienthypophysial-gonadotropic action (acute action).

DISCLOSURE OF INVENTION

[0006] The present inventors produced various nitrogen-containingheterocyclic derivatives, investigated their actions, and found thatsome nitrogen-containing heterocyclic compounds possess excellentGnRH-antogonizing activity. The inventors conducted furtherinvestigation based on this finding, and developed the presentinvention. Accordingly, the present invention relates to:

[0007] [1] A compound of the formula (I):

[0008]  wherein

[0009] one of A and D represents a nitrogen atom and the otherrepresents a carbon atom, or both represent a nitrogen atom;

[0010] B represents a nitrogen atom or a carbon atom;

[0011] m represents an integer from 0 to 3;

[0012] R¹, R² and R³ each represents (i) hydrogen or (ii) a group boundvia a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;

[0013] R⁴ represents a group bound via a carbon atom;

[0014] R⁵ represents (i) hydrogen, (ii) halogen or (iii) a group boundvia a carbon atom or an oxygen atom;

[0015] R⁶ represents hydrogen or a group bound via a carbon atom;

[0016] R⁷ represents a homocyclic group which may be substituted or aheterocyclic group which may be substituted; and

[0017] each dotted line represents a single bond or a double bond,[hereinafter sometimes referred to briefly as compound (I)] or a saltthereof;

[0018] [2] a compound of the above [1] or a salt thereof,

[0019]  wherein

[0020] R¹, R² and R³ each is

[0021] (1) hydrogen,

[0022] (2) a hydrocarbon group which may be substituted,

[0023] (3) an acyl group which may be substituted,

[0024] (4) a heterocyclic group having a bond in a carbon atom thereofwhich may be substituted,

[0025] (5) a group of the formula: —COOR²¹ wherein R²¹ is hydrogen, ahydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted,

[0026] (6) a group of the formula: —CO—NR¹⁵R¹⁶ wherein R¹⁵ is hydrogen,a hydrocarbon group which may be substituted or a C₁₋₁₀ alkoxy group;and R¹⁶ is hydrogen or a hydrocarbon group which may be substituted; orR¹⁵ and R¹⁶ form, taken together with the adjacent nitrogen atom, acyclic amino group which may be substituted,

[0027] (7) a cyano group,

[0028] (8) a nitro group,

[0029] (9) a group of the formula: —NR⁸R⁹ wherein R⁸ is (i) hydrogen,(ii) a hydrocarbon group which may be substituted, (iii) an acyl groupwhich may be substituted, (iv) a group of the formula: —O—R¹³ whereinR¹³ is hydrogen, a C₁₋₁₀ hydrocarbon group which may be substituted, aC₁₋₂₀ acyl group which may be substituted, a C₁₋₂₀ alkylsulfonyl groupwhich may be substituted, a C₆₋₁₄ arylsulfonyl group which may besubstituted or a heterocyclic group which may be substituted, (v) aheterocyclic group which may be substituted or (vi) a group of theformula: —S(O)t-R¹² wherein t is an integer from 0 to 2, and R¹² ishydrogen or a C₁₋₁₀ hydrocarbon group which may be substituted;

[0030] R⁹ is hydrogen, a hydrocarbon group which may be substituted oran acyl group which may be substituted; or

[0031] R⁸ and R⁹ form, taken together with the adjacent nitrogen atom, acyclic amino group which may be substituted,

[0032] (10) a group of the formula: —O—R¹³ wherein R¹³ is as definedabove, or

[0033] (11) a group of the formula: —S(O)t-R¹⁴ wherein t is an integerfrom 0 to 2, and R¹⁴ is hydrogen, a hydrocarbon group which may besubstituted or a heterocyclic group which may be substituted;

[0034] R⁴ is

[0035] (1) a hydrocarbon group which may be substituted,

[0036] (2) an acyl group which may be substituted,

[0037] (3) a heterocyclic group having a bond in a carbon atom thereofwhich may be substituted,

[0038] (4) a group of the formula: —COOR²¹ wherein R²¹ is as definedabove,

[0039] (5) a group of the formula: —CO—NR¹⁵R¹⁶ wherein each symbol is asdefined above, or

[0040] (6) a cyano group;

[0041] R⁵ is

[0042] (1) hydrogen,

[0043] (2) halogen,

[0044] (3) a hydrocarbon group which may be substituted,

[0045] (4) an acyl group which may be substituted,

[0046] (5) a heterocyclic group having a bond in a carbon atom thereofwhich may be substituted,

[0047] (6) a group of the formula: —COOR²¹ wherein R²¹ is as definedabove,

[0048] (7) a group of the formula: —CO—NR¹⁵R¹⁶ wherein each symbol is asdefined above,

[0049] (8) a cyano group, or

[0050] (9) a group of the formula: —O—R¹³ wherein R¹³ is as definedabove;

[0051] R⁶ is

[0052] (1) hydrogen,

[0053] (2) a hydrocarbon group which may be substituted,

[0054] (3) an acyl group which may be substituted,

[0055] (4) a heterocyclic group having a bond in a carbon atom thereofwhich may be substituted,

[0056] (5) a group of the formula: —COOR²¹ wherein R²¹ is as definedabove,

[0057] (6) a group of the formula: —CO—NR¹⁵R¹⁶ wherein each symbol is asdefined above, or

[0058] (7) a cyano group;

[0059] R⁷ is (i) a C₆₋₁₀ aryl or C₃₋₇ cycloalkyl group, each of whichmay be substituted by 1 to 6 substituents selected from the groupconsisting of (1) C₁₋₁₅ alkyl which may be substituted by 1 to 3halogen, (2) C₃₋₁₀ cycloalkyl, (3) C₂₋₁₀ alkenyl, (4) C₂₋₁₀ alkynyl, (5)C₃₋₁₀ cycloalkenyl, (6) C₆₋₁₀ aryl, (7) C₇₋₂₀ aralkyl, (8) nitro, (9)hydroxy, (10) mercapto, (11) oxo, (12) thioxo, (13) cyano, (14)carbamoyl, (15) carboxyl, (16) C₁₋₆ alkoxy-carbonyl, (17) sulfo, (18)halogen, (19) C₁₋₆ alkoxy, (20) C₆₋₁₀ aryloxy, (21) C₁₋₆ alkanoyloxy,(22) C₁₋₆ alkylthio, (23) C₆₋₁₀ arylthio, (24) C₁₋₆ alkylsulfinyl, (25)C₆₋₁₀ arylsulfinyl, (26) C₁₋₆ alkylsulfonyl, (27) C₆₋₁₀ arylsulfonyl,(28) amino, (29) C₁₋₆ alkanoylamino, (30) mono- or di-C₁₋₄ alkylamino,(31) C₃₋₈ cycloalkylamino, (32) C₆₋₁₀ arylamino, (33) C₁₋₆ alkanoyl,(34) C₆₋₁₀ aryl-carbonyl and (35) 5- to 6-membered heterocyclic group,or (ii) a heterocyclic group which may be substituted,

[0060] in which “hydrocarbon group” is a C₁₋₂₀ hydrocarbon groupselected from C₁₋₁₅ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl and C₇₋₂₀ aralkyl;

[0061] “C₁₋₁₀ hydrocarbon group” is a C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀ aryl orphenyl-C₁₋₄ alkyl group;

[0062] “acyl group” and “C₁₋₂₀ acyl group” each is formyl, C₁₋₆alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl, C₆₋₁₄aryloxy-carbonyl, C₆₋₁₄ aryl-C₁₋₆ alkyl-carbonyl, C₆₋₁₄ aryl-C₁₋₆alkoxy-carbonyl, C₂₋₄ alkenyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl ortricyclic bridged C₉₋₁₀ hydrocarbon-carbonyl;

[0063] “heterocyclic group” is (1) a 5- to 8-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms,nitrogen atoms in addition to carbon atoms, (2) a bi- or tri-cycliccondensed heterocyclic group resulting from condensation of 2 or 3 ofthe above (1) heterocyclic group, whether identical or not, or (3) a bi-or tri-cyclic condensed heterocyclic group resulting from condensationof the above (1) heterocyclic group and 1 or 2 benzene rings;

[0064] “cyclic amino group” is a 5- to 7-membered cyclic amino groupoptionally containing 1 to 3 hetero atoms selected from oxygen atoms,sulfur atoms, nitrogen atoms in addition to carbon atoms and a nitrogenatom;

[0065] “substituent(s)” for the “hydrocarbon group which may besubstituted”, the “C₁₋₁₀ hydrocarbon group which may be substituted”,the “acyl group which may be substituted”, “C₁₋₂₀ acyl group which maybe substituted”, the “C₁₋₂₀ alkylsulfonyl group which may besubstituted” or the “C₆₋₁₄ arylsulfonyl group which may be substituted”is selected from 1 to 6 of (1) halogen, (2) nitro, (3) nitroso, (4)cyano, (5)(i) C₁₋₆ alkyl which may be substituted by 1 to 3 substituentsselected from the group consisting of hydroxy, C₁₋₆ alkoxy, C₁₋₃alkoxy-C₁₋₃ alkoxy, C₁₋₃ alkylthio, hydroxy-C₁₋₃ alkoxy, C₁₋₆alkyl-carbonyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbamoyl, 5- to8-membered heterocyclic group and halogen, (ii) C₁₋₄ alkanoyl or C₂₋₄alkenoyl, (iii) C₆₋₁₄ aryl-C₁₋₆ alkyl which may be substituted by 1 to 3substituents selected from the group consisting of halogen, C₁₋₃ alkoxyand C₁₋₄ alkyl, (iv) C₆₋₁₄ aryl which may be substituted by 1 to 3halogen, (v) C₂₋₆ alkenyl, (vi) C₃₋₇ cycloalkyl, (vii) C₁₋₃alkoxy-carbonyl, (viii) mono- or di-C₁₋₆ alkyl amino, (ix) C₂₋₆ alkenylamino, (x) C₁₋₃ alkoxy-carbonyl, (xi) formyl or C₁₋₆ alkyl-carbonyl, or(xii) hydroxy which may be substituted by C₃₋₆ cycloalkyloxy-carbonyl,(6) a group of the formula: —S(O)t-R¹⁷ wherein t is an integer from 0 to2, and R¹⁷ is (i) hydrogen or (ii) a C₁₋₆ alkyl, C₆₋₁₄ aryl or C₇₋₂₀aralkyl group which may be substituted by 1 to 3 substituents selectedfrom the group consisting of halogen, nitro, cyano, hydroxy, oxo,thioxo, carboxy, cyano-C₆₋₁₄ aryl and halogeno-C₆₋₁₄ aryl, (7) a groupof the formula: —NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ each is hydrogen, C₁₋₆alkyl, C₁₋₆ alkylamino-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, phenyl, phenyl-C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₃₋₆ alkenoyl,C₄₋₇ cycloalkyl-carbonyl, phenyl-C₁₋₆ alkyl-carbonyl, C₁₋₆alkoxy-carbonyl, phenyl-C₁₋₆ alkoxy-carbonyl or 5- to 8-memberedheterocyclic group, (8) a group of the formula: —CO—R²⁰ wherein R²⁰ is(i) hydrogen, (ii) hydroxy, (iii) C₁₋₁₀ alkyl or (iv) C₁₋₆ alkoxy whichmay be substituted by C₆₋₁₄ aryl which may be substituted by 1 to 3substituents selected from the group consisting of halogen and nitro,(v) C₃₋₆ cycloalkyl, (vi) C₆₋₁₄ aryl, (vii) C₆₋₁₄ aryloxy, (viii) C₇₋₂₀aralkyl, (ix) a group of the formula: —NR¹⁰R¹¹ wherein R¹⁰ is hydrogen,a C₁₋₁₀ hydrocarbon group which may be substituted, a C₁₋₂₀ acyl groupwhich may be substituted, a group of the formula: —O—R¹³ wherein R¹³ isas defined above, a heterocyclic group which may be substituted or agroup of the formula: —S(O)t-R¹² wherein each symbol is as definedabove; and R¹¹ is hydrogen or a C₁₋₁₀ hydrocarbon group; or R¹⁰ and R¹¹form, taken together with the adjacent nitrogen atom, a cyclic aminogroup which may be substituted, or (x) 5- to 8-membered heterocyclicgroup, (9) 5- to 8-membered heterocyclic group which may be substitutedby 1 to 3 substituents selected form the group consisting of hydroxy,amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆alkyl, (10) sulfo, (11) C₆₋₁₄ aryl which may be substituted by 1 to 3substituents selected form the group consisting of hydroxy, amino, mono-or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (12)C₃₋₇ cycloalkyl which may be substituted by 1 to 3 substituents selectedform the group consisting of hydroxy, amino, mono- or di-C₁₋₄alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (13) C₁₋₆alkylenedioxy, (14) oxo, (15) thioxo, (16) C₂₋₄ alkynyl which may besubstituted by 1 to 3 substituents selected form the group consisting ofhydroxy, amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitroand C₁₋₆ alkyl, (17) C₃₋₁₀ cycloalkyl which may be substituted by 1 to 3substituents selected form the group consisting of hydroxy, amino, mono-or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (18)C₂₋₁₀ alkenyl which may be substituted by 1 to 3 substituents selectedform the group consisting of hydroxy, amino, mono- or di-C₁₋₄alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (19) C₇₋₂₀aralkyl which may be substituted by 1 to 3 substituents selected formthe group consisting of hydroxy, amino, mono- or di-C₁₋₄ alkylamino,C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (20) amidino and (21) azido;

[0066] “substituent(s)” for the “heterocyclic group which may besubstituted” or the “heterocyclic group having a bond in a carbon atomthereof which may be substituted” is selected from 1 to 6 of (1) C₁₋₆alkyl, (2) C₂₋₆ alkenyl, (3) C₂₋₆ alkynyl, (4) C₃₋₆ cycloalkyl, (5) C₅₋₇cycloalkenyl, (6) C₆₋₁₀ aryl-C₁₋₅ alkyl, (7) C₆₋₁₄ aryl, (8) C₁₋₆alkoxy, (9) C₆₋₁₄ aryloxy, (10) C₁₋₆ alkanoyl, (11) C₆₋₁₄ aryl-carbonyl,(12) C₁₋₆ alkanoyloxy, (13) C₆₋₁₄ aryl-carbonyloxy, (14) carboxyl, (15)C₁₋₆ alkoxy-carbonyl, (16) carbamoyl, (17) N-mono-C₁₋₄ alkylcarbamoyl,(18) N,N-di-C₁₋₄ alkylcarbamoyl, (19) 3- to 6-membered cyclicaminocarbonyl, (20) halogen, (21) mono-, di- or tri-halogeno-C₁₋₄ alkyl,(22) oxo, (23) amidino, (24) imino, (25) amino, (26) mono- or di-C₁₋₄alkylamino, (27) 3- to 6-membered cyclic amino, (28) C₁₋₆ alkanoylamino,(29) benzamido, (30) carbamoylamino, (31) N-C₁₋₄ alkylcarbamoylamino,(32) N,N-di-C₁₋₄ alkylcarbamoylamino, (33) C₁₋₃ alkylenedioxy, (34)—B(OH)₂, (35) hydroxy, (36) epoxy, (37) nitro, (38) cyano, (39)mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43) sulfamoyl, (44)C₁₋₆ alkylsulfamoyl, (45) di-C₁₋₆ alkylsulfamoyl, (46) C₁₋₆ alkylthio,(47) phenylthio, (48) C₁₋₆ alkylsulfinyl, (49) phenylsulfinyl, (50) C₁₋₆alkylsulfonyl and (51) phenylsulfonyl; and

[0067] “substituent(s)” for the “cyclic amino group which may besubstituted” is selected from 1 to 3 of C₁₋₆ alkyl, C₆₋₁₄ aryl,phenyl-C₁₋₄ alkyl, benzhydryl, C₁₋₆ alkyl-carbonyl, C₆₋₁₄ aryl-carbonyland C₁₋₆ alkoxy-carbonyl;

[0068] [3] a compound of the above [1] or a salt thereof, wherein A is anitrogen atom;

[0069] [4] a compound of the above [1] or a salt thereof, wherein B is anitrogen atom;

[0070] [5] a compound of the above [1] or a salt thereof, wherein D is anitrogen atom;

[0071] [6] a compound of the above [1] or a salt thereof, wherein m is1;

[0072] [7] a compound of the above [1] or a salt thereof, wherein R¹ is(1) a C₁₋₁₅ alkyl group which may be substituted, (2) a C₃₋₁₀ cycloalkylgroup which may be substituted, (3) a C₂₋₁₀ alkenyl group which may besubstituted, (4) a C₂₋₁₀ alkynyl group which may be substituted, (5) aC₃₋₁₀ cycloalkenyl group which may be substituted, (6) a C₆₋₁₄ arylgroup which may be substituted, (7) a C₇₋₂₀ aralkyl group which may besubstituted, (8) a C₁₋₂₀ acyl group which may be substituted, (9) anitro group, (10) a group of the formula: —NR¹⁰R¹¹ wherein R¹⁰ ishydrogen, a C₁₋₁₀ hydrocarbon group which may be substituted, a C₁₋₂₀acyl group which may be substituted, a hydroxy group which may besubstituted, a heterocyclic group which may be substituted or a group ofthe formula: —S(O)t-R¹² wherein t is an integer from 0 to 2, and R¹² ishydrogen or a C₁₋₁₀ hydrocarbon group which may be substituted; R¹¹ ishydrogen or a C₁₋₁₀ hydrocarbon group; or R¹⁰ and R¹¹ form, takentogether with the adjacent nitrogen atom, a cyclic amino group which maybe substituted, or (11) a group of the formula: —O—R¹³ wherein R¹³ ishydrogen, a C₁₋₁₀ hydrocarbon group which may be substituted, a C₁₋₂₀acyl group which may be substituted, a C₁₋₂₀ alkylsulfonyl group whichmay be substituted, a C₆₋₁₄ arylsulfonyl group which may be substituted,or a heterocyclic group which may be substituted; and R² and R³ each ishydrogen;

[0073] [8] a compound of the above [1] or a salt thereof, wherein R² andR³ each is hydrogen;

[0074] [9] a compound of the above [8] or a salt thereof, wherein theposition of R¹ is para-position;

[0075] [10] a compound of the above [1] or a salt thereof, wherein R¹ is(1) an amino group which may be substituted by (i) carbamoyl which maybe substituted by C₁₋₆ alkyl or C₁₋₆ alkoxy, or (ii) C₁₋₆alkyl-carbonyl, or (2) a C₁₋₆ alkoxy group which may be substituted byC₃₋₆ cycloalkyl;

[0076] [11] a compound of the above [1] or a salt thereof, wherein R⁴ isa C₁₋₁₅ alkyl group which may be substituted, a C₃₋₁₀ cycloalkyl groupwhich may be substituted, a C₂₋₁₀ alkenyl group which may besubstituted, a C₂₋₁₀ alkynyl group which may be substituted, a C₃₋₁₀cycloalkenyl group which may be substituted, a C₆₋₁₄ aryl group whichmay be substituted or a C₇₋₂₀ aralkyl group which may be substituted;

[0077] [12] a compound of the above [1] or a salt thereof, wherein R⁴ isa C₁₋₆ alkyl group which may be substituted;

[0078] [13] a compound of the above [1] or a salt thereof, wherein R⁴ isa C₁₋₆ alkyl group which may be substituted by halogen, hydroxy whichmay be substituted or amino which may be substituted;

[0079] [14] a compound of the above [1] or a salt thereof, wherein R⁴ isa group of the formula: —(CH₂)n-NR¹OR¹¹ wherein n is an integer from 1to 3; R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a hydroxygroup which may be substituted, a heterocyclic group which may besubstituted, or a group of the formula: —S(O)t-R¹² wherein t is aninteger from 0 to 2, and R¹² is hydrogen or a C₁₋₁₀ hydrocarbon groupwhich may be substituted; and R¹l is hydrogen or a C₁₋₁₀ hydrocarbongroup; or R¹⁰ and R¹¹ form, taken together with the adjacent nitrogenatom, a cyclic amino group which may be substituted;

[0080] [15] a compound of the above [1] or a salt thereof, wherein R⁴ isa N—C₁₋₆ alkyl-N-benzylaminomethyl group;

[0081] [16] a compound of the above [1] or a salt thereof, wherein R⁵ ishydrogen, halogen, a C₁₋₁₅ alkyl group which may be substituted, a C₃₋₁₀cycloalkyl group which may be substituted, a C₂₋₁₀ alkenyl group whichmay be substituted, a C₂₋₁₀ alkynyl group which may be substituted, aC₃₋₁₀ cycloalkenyl group which may be substituted, a C₆₋₁₄ aryl groupwhich may be substituted, a C₇₋₂₀ aralkyl group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a carboxygroup which may be esterified or amidated, or a group of the formula:—O—R¹³ wherein R¹³ is hydrogen or a C₁₋₁₅ alkyl group which may besubstituted, a C₃₋₁₀ cycloalkyl group which may be substituted, a C₂₋₁₀alkenyl group which may be substituted, a C₂₋₁₀ alkynyl group which maybe substituted, a C₃₋₁₀ cycloalkenyl group which may be substituted, aC₆₋₁₄ aryl group which may be substituted, a C₇₋₂₀ aralkyl group whichmay be substituted, a C₁₋₂₀ acyl group which may be substituted, a C₁₋₂₀alkylsulfonyl group which may be substituted, a C₆₋₁₄ arylsulfonyl groupwhich may be substituted or a heterocyclic group which may besubstituted;

[0082] [17] a compound of the above [1] or a salt thereof, wherein R⁵ is(1) a C₁₋₆ alkoxy-carbonyl group, (2) a C₆₋₁₀ aryl group which may besubstituted by halogen or C₁₋₆ alkoxy, or (3) a phenyl-C₁₋₃ alkyl group;

[0083] [18] a compound of the above [1] or a salt thereof, wherein R⁶ ishydrogen, a C₁₋₁₅ alkyl group which may be substituted, a C₃₋₁₀cycloalkyl group which may be substituted, a C₂₋₁₀ alkenyl group whichmay be substituted, a C₂₋₁₀ alkynyl group which may be substituted, aC₃₋₁₀ cycloalkenyl group which may be substituted, a C₆₋₁₄ aryl groupwhich may be substituted or a C₇₋₂₀ aralkyl group which may besubstituted;

[0084] [19] a compound of the above [1] or a salt thereof, wherein R⁶ ishydrogen or a C₁₋₆ alkyl group;

[0085] [20] a compound of the above [1] or a salt thereof, wherein R⁷ isa C₆₋₁₄ aryl group which may be substituted;

[0086] [21] a compound of the above [1] or a salt thereof, wherein R⁷ isa phenyl group which may be substituted by halogen(s);

[0087] [22] a compound of the above [1] or a salt thereof, wherein oneof A and D represents a nitrogen atom and the other represents a carbonatom, or both represent a nitrogen atom; B represents a nitrogen atom ora carbon atom; m represents an integer from 0 to 3; R¹, R² and R³ eachrepresents (i) hydrogen or (ii) a group bound via a carbon atom, anitrogen atom, an oxygen atom or a sulfur atom; R⁴ represents a groupbound via a carbon atom; R⁵ represents hydrogen or a group bound via acarbon atom or an oxygen atom; R⁶ represents hydrogen or a group boundvia a carbon atom; R⁷ represents a homocyclic group which may besubstituted or a heterocyclic group which may be substituted; and eachdotted line represents a single bond or a double bond;

[0088] [23] a compound of the above [1], which is represented by theformula (e):

[0089]  wherein each symbol is as defined above, or a salt thereof;

[0090] [24] a compound of the above [23] or a salt thereof, wherein R⁴is a group of the formula: —(CH₂)n-NR¹⁰R¹¹ wherein n is an integer from1 to 3; R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a hydroxygroup which may be substituted, a heterocyclic group which may besubstituted, or a group of the formula: —S(O)t-R¹² wherein t is aninteger from 0 to 2, and R¹² is hydrogen or a C₁₋₁₀ hydrocarbon groupwhich may be substituted; and R¹¹ is hydrogen, a C₁₋₁₀ hydrocarbon groupor a C₁₋₂₀ acyl group which may be substituted; or R¹⁰ and R¹¹ form,taken together with the adjacent nitrogen atom, a cyclic amino groupwhich may be substituted;

[0091] [25] a compound of the above [1], which is represented by theformula:

[0092]  wherein each symbol is as defined above, or a salt thereof;

[0093] [26] a compound of the above [25] or a salt thereof, wherein R¹is (1) an amino group which may be substituted by (i) carbamoyl whichmay be substituted by C₁₋₆ alkyl or C₁₋₆ alkoxy, or (ii) C₁₋₆alkyl-carbonyl, or (2) a C₁₋₆ alkoxy group which may be substituted byC₃₋₆ cycloalkyl;

[0094] R⁴ is a N—C₁₋₆ alkyl-N-benzylaminomethyl group R⁵ is (1) a C₁₋₆alkoxy-carbonyl group, (2) a C₆₋₁₀ aryl group which may be substitutedby halogen or C₁₋₆ alkoxy, or (3) a phenyl-C₁₋₃ alkyl group; and

[0095] R⁶ is hydrogen;

[0096] [27] a compound of the above [25] or a salt thereof, wherein

[0097] R¹ is

[0098] (1) a nitro group,

[0099] (2) an amino group which may be substituted by 1 or 2substituents selected from the group consisting of (i) C₁₋₆ alkyl whichmay be substituted by hydroxy, (ii) C₁₋₆ alkyl-carbonyl which may besubstituted by hydroxy, halogen or thienyl, (iii) C₆₋₁₀ aryl-carbonylwhich may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, (iv)C₃₋₆ cycloalkyl-carbonyl, (v) C₂₋₄ alkenyl-carbonyl, (vi) C₁₋₆alkoxy-carbonyl, (vii) C₁₋₆ alkylamino-carbonyl, (viii) C₁₋₆alkoxyamino-carbonyl, (ix) phenylaminocarbonyl, (x) anisoxazolylcarbonyl, thienylcarbonyl, thiazolylcarbonyl,pyrazolylcarbonyl or furylcarbonyl group which may be substituted by 1or 2 substituents selected from the group consisting of C₁₋₆ alkyl,nitro and C₁₋₆ alkoxy, (xi) pyridylcarbonyl, (xii) C₁₋₆ alkylsulfonyl,(xiii) thienylsulfonyl and (xiv) phenylsulfonyl which may be substitutedby C₁₋₆ alkyl,

[0100] (3) a pyrrolyl group or

[0101] (4) a hydroxy group which may be substituted by C₁₋₆ alkyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl or C₁₋₆ alkyl-carbonyl;

[0102] R⁴ is a C₁₋₆ alkyl group which may be substituted by 1 or 2substituents selected from the group consisting of (1) halogen, (2)hydroxy and (3) amino which may be substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₃ alkyl anddi-C₁₋₆ alkylamino-C₁₋₃ alkyl;

[0103] R⁵ is (1) halogen, (2) a phenyl group which may be substituted byhalogen or C₁₋₆ alkyl, or (3) a carbonyl group substituted by (i) C₁₋₆alkyl, (ii) amino substituted by C₁₋₆ alkyl and C₁₋₆ alkoxy or (iii)C₁₋₆ alkoxy; and

[0104] R⁶ is hydrogen or a C₁₋₃ alkyl group;

[0105] [28]8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(methoxyaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester, or salts thereof;

[0106] [29] a process for producing a compound of the above [23] or asalt thereof, which comprises reacting a compound of the formula (iv):

[0107]  wherein each symbol is as defined above, or a salt thereof, witha compound of the formula: X²—(CH₂)m-R⁷ wherein X² is a leaving group;and the other symbols are as defined above, or a salt thereof;

[0108] [30] a pharmaceutical composition which comprises a compound ofthe above [1] or a salt thereof;

[0109] [31] a composition of the above [30] which is agonadotropin-releasing hormone antagonist;

[0110] [32] a composition of the above [30] for preventing and/ortreating a sex hormone dependent disease;

[0111] [33] a composition of the above [30] for preventing and/ortreating a sex hormone dependent cancer.

[0112] [34] a composition of the above [30] for preventing and/ortreating prostatic cancer, uterine cancer or breast cancer;

[0113] [35] a composition of the above [30] for preventing and/ortreating prostatic hypertrophy, endometriosis, hysteromyoma orprecocious puberty;

[0114] [36] a composition of the above [30] which is a pregnancyregulator;

[0115] [37] a composition of the above [30] which is a menstruationcycle regulator;

[0116] [38] a method for antagonizing gonadotropin-releasing hormone ina mammal in need thereof which comprises administering to said mammal aneffective amount of a compound of the above [1] or a salt thereof with apharmaceutically acceptable excipient, carrier or diluent;

[0117] [39] use of a compound of the above [1] or a salt thereof formanufacturing a pharmaceutical composition for antagonizinggonadotropin-releasing hormone; and so forth.

[0118] In the above formulas, the group bound via a carbon atom includes(1) a hydrocarbon group which may be substituted, (2) an acyl groupwhich may be substituted, (3) a heterocyclic group having a bond in acarbon atom thereof which may be substituted, (4) a carboxy group whichmay be esterified or amidated, or (5) a cyano group.

[0119] In the above formulas, the group bound via a nitrogen atomincludes (1) a nitro group or (2) a group of the formula: —NR⁸R⁹ whereinR⁸ represents hydrogen, a hydrocarbon group which may be substituted, anacyl group which may be substituted, a hydroxy group which may besubstituted, a heterocyclic group which may be substituted, or a groupof the formula: —S(O)t-R¹² wherein t represents an integer from 0 to 2,and R¹² represents hydrogen or a C₁₋₁₀ hydrocarbon group which may besubstituted; R⁹ represents hydrogen, a hydrocarbon group which may besubstituted or an acyl group which may be substituted; or R⁸ and R⁹ mayform, taken together with the adjacent nitrogen atom, a cyclic aminogroup which may be substituted.

[0120] In the above formulas, the group bound via an oxygen atomincludes a hydroxy group which may be substituted. The hydroxy groupwhich may be substituted is represented by the formula: —O—R¹³ whereinR¹³ represents hydrogen or a C₁₋₁₀ hydrocarbon group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a C₁₋₂₀alkylsulfonyl group which may be substituted, a C₆₋₁₄ arylsulfonyl groupwhich may be substituted or a heterocyclic group which may besubstituted.

[0121] In the above formulas, the group bound via a sulfur atom is agroup of the formula: —S(O)t-R¹⁴ wherein t represents an integer from 0to 2, and R¹⁴ represents hydrogen or a hydrocarbon group which may besubstituted or a heterocyclic group which may be substituted.

[0122] The above-described carboxy group which may be esterified is agroup of the formula: —COO—R²¹ wherein R²¹ represents hydrogen or ahydrocarbon group which may be substituted.

[0123] The above-described carboxy group which may be amidated is agroup of the formula: —CO—NR¹⁵R¹⁶ wherein R¹⁵ represents hydrogen, ahydrocarbon group which may be substituted, an alkoxy group; R¹⁶represents hydrogen or a hydrocarbon group which may be substituted; orR¹⁵ and R¹⁶ may form, taken together with the adjacent nitrogen atom, acyclic amino group which may be substituted. The carboxy group which maybe amidated is preferably exemplified by a group represented by —CONH₂,and mono- or di-C₁₋₁₅ alkylcarbamoyl groups, preferably mono- ordi-C₁₋₁₀ alkylcarbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl,hexylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl).

[0124] The hydrocarbon group in the above-described hydrocarbon groupwhich may be substituted is preferably a C₁₋₂₀ hydrocarbon group,preferably C₁₋₁₀ hydrocarbon group. The C₁₋₂₀ hydrocarbon group isexemplified by (1) C₁₋₁₅ alkyl groups (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc.;preferably C₁₋₁₀ alkyls, more preferably C₁₋₆ alkyl groups), (2) C₃₋₁₀cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; preferably C₃₋₆cycloalkyl groups), (3) C₂₋₁₀ alkenyl groups (e.g., vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl,hexatrienyl, 3-octenyl, etc.; preferably C₂₋₆ alkenyl groups, (4) C₂₋₁₀alkynyl groups (e.g., ethynyl, 2-propynyl, isopropynyl, butynyl,t-butynyl, 3-hexynyl, etc.; preferably C₂₋₆ alkynyl groups), (5) C₃₋₁₀cycloalkenyl groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl,etc.; preferably C₃₋₆ cycloalkenyl groups), (6) C₆₋₁₄ aryl groups (e.g.,phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.;preferably phenyl and naphthyl), and (7) C₇₋₂₀ aralkyl groups (e.g.,C₆₋₁₄ aryl-C₁₋₆ alkyls such as benzyl, phenethyl and benzhydryl,preferably phenyl-C₁₋₆ alkyls such as benzyl and phenethyl).

[0125] Such hydrocarbon groups may have 1 to 6, preferably 1 to 5, andmore preferably 1 to 3 substituents at any possible positions. Suchsubstituents include, for example, (1) halogen, (2) nitro, (3) nitroso,(4) cyano, (5) hydroxy which may be substituted, for example, hydroxywhich may be substituted by (i) C₁₋₆ alkyl [the C₁₋₆ alkyl may besubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C, alkoxy, C₁₋₃ alkylthio,hydroxy-C₁₋₃ alkoxy, C₁₋₆ alkyl-carbonyl, carboxy, carbamoyl, C₁₋₆alkyl-carbamoyl, 5- to 8-membered heterocyclic group (same as the “5- to8-membered heterocyclic group containing 1 to 4 hetero atoms selectedfrom oxygen atoms, sulfur atoms, nitrogen atoms etc., in addition tocarbon atoms” described below) and halogen, etc.], (ii) C₁₋₄ acyl (e.g.,C₁₋₄ alkanoyl, C₂₋₄ alkenoyl), (iii) C₇₋₂₀ aralkyl (the C₇₋₂₀ aralkyl isC₆₋₁₄ aryl-C₁₋₆ alkyl and may be substituted by 1 to 3, preferably 1halogen, C₁₋₃ alkoxy or C₁₋₄ alkyl), (iv) C₆₋₁₄ aryl (the C₆₋₁₄ aryl maybe substituted by 1 to 3, preferably 1 halogen), (v) C₂₋₆ alkenyl, (vi)C₃₋₇ cycloalkyl, (vii) C₁₋₃ alkoxy-carbonyl, (viii) mono- or di-C₁₋₆alkylamino, (ix) C₂₋₆ alkenylamino, (x) C₁₋₃ alkoxy-carbonyl, (xi) C₁₋₆alkyl-carbonyl or (xii) C₃₋₆ cycloalkyloxy-carbonyl, (6) a group of theformula: —S(O)t-R¹⁷ wherein t represents an integer from 0 to 2; R¹⁷represents hydrogen or a hydrocarbon group which may be substituted by 1to 3, preferably 1 substituent (e.g., halogen, nitro, cyano, hydroxy,oxo, thioxo, carboxy, cyano-C₆₋₁₄ aryl, halogeno-C₆₋₁₄ aryl) at anypossible positions; the hydrocarbon group is preferably C₁₋₂₀hydrocarbon group, more preferably C₁₋₆ alkyl, C₆₋₁₄ aryl or C₇₋₂₀aralkyl, (7) amino which may be substituted, for example, a group of theformula: —NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ each represents hydrogen, C₁₋₆alkyl, C₁₋₆ alkylamino-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, phenyl, phenyl-C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₃₋₆ alkenoyl,C₄₋₇ cycloalkyl-carbonyl, phenyl-C₁₋₆ alkyl-carbonyl, C₁₋₆alkyloxy-carbonyl, phenyl-C₁₋₆ alkoxy-carbonyl, or a 5- to 8-memberedheterocyclic group (the same as the “5- to 8-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms,nitrogen atoms etc., in addition to carbon atoms” described below.) (8)a group of the formula: —CO—R²⁰ wherein R²⁰ represents (i) hydrogen,(ii) hydroxy, (iii) C₁₋₁₀ alkyl, (iv) C₁₋₆ alkoxy (this alkoxy may besubstituted by C₆₋₁₄ aryl which may be substituted by 1 to 3, preferably1 halogen or nitro, at any possible position), (v) C₃₋₆ cycloalkyl, (vi)C₆₋₁₄ aryl, (vii) C₆₋₁₄ aryloxy, (viii) C₇₋₂₀ aralkyl, (ix) group of theformula: —NR¹⁰R¹¹ wherein R¹⁰ and R¹¹ have the same definitions as thosegiven above, or (x) 5- to 8-membered heterocyclic group (the same as theabove-described “5- to 8-membered heterocyclic group containing 1 to 4hetero atoms selected from oxygen atoms, sulfur atoms, nitrogen atomsetc., in addition to carbon atoms”) (e.g., C₁₋₆ alkanoyl, C₃₋₆ alkenoyl,C₁₋₆ alkoxy-carbonyl, etc. are preferred), (9) 5- to 8-memberedheterocyclic group containing 1 to 4 hetero atoms selected from nitrogenatoms, oxygen atoms and sulfur atoms, (10) sulfo, (11) C₆₋₁₄ aryl, (12)C₃₋₇ cycloalkyl, (13) C₁₋₆ alkylenedioxy (e.g., methylenedioxy,ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy), (14) oxo, (15)thioxo, (16) C₂₋₄ alkynyl, (17) C₃₋₁₀ cycloa ky1, (18) C₂₋₁₀ alkenyl(preferably C₂₋₆ alkenyl), (19) C₇₋₂₀ aralkyl (C₆₋₁₄ aryl-C₁₋₆ alkyl),(20) amidino, and (21) azide.

[0126] Of the above-mentioned substituents on hydrocarbon groups havingsubstituents, (9) 5- to 8-membered heterocyclic group containing 1 to 4hetero atoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, (11) C₆₋₁₄ aryl, (12) C₃₋₇ cycloalkyl, (16) C₂₋₄ alkynyl, (17)C₃₋₁₀ cycloalkyl, (18) C₂₋₁₀ alkenyl, (19) C₇₋₂₀ aralkyl etc. mayfurther have 1 to 4, preferably 1 to 3 substituents at any possiblepositions. Such substituents which may be further contained include, forexample, 1 to 3, preferably 1 to 2 groups selected from the groupconsisting of (1) hydroxy, (2) amino, (3) mono- or di-C₁₋₄ allylamino(e.g., methylamino, ethylamino, propylamino, dimethylamino,diethylamino), (4) C₁₋₄ alkoxy, (5) halogen, (6) nitro, and (7) C₁₋₆alkyl, etc.

[0127] When the hydrocarbon group is a cycloalkyl, cycloalkenyl, aryl oraralkyl group, it may be substituted by 1 to 3 C₁₋₆ alkyl. The C₁₋₆alkyl may be further substituted by 1 to 3 substituents selected fromthe group consisting of hydroxy, oxo, C₁₋₃ alkoxy, C₁₋₃ alkylthio,halogen, and carbamoyl, etc.

[0128] Such substituted C₁₋₆ alkyl is exemplified by formyl (resultingfrom methyl substitution by oxo), carboxy (resulting from methylsubstitution by oxo and hydroxy), C₁₋₆ alkoxycarbonyl (resulting frommethyl substitution by oxo and alkoxy) (e.g., C₁₋₆ alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl), hydroxy-C₁₋₆alkyl (e.g., hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl),and C₁₋₃ alkoxy-C₁₋₆ alkyl (e.g., methoxymethyl, ethoxymethyl,ethoxybutyl, propoxymethyl, propoxyhexyl), etc.

[0129] Although the number of such substituents ranges from 1 to 6, itis preferably 1 to 5, more preferably 1 to 3, and most preferably 1 to2. The number of substituents which may be further contained in suchsubstituents is preferably 1 to 4, more preferably 1 to 3, and mostpreferably 1 to 2.

[0130] The acyl group in the above acyl group which may be substituted,which is mentioned to exemplify the group bound via a carbon atom, R⁸and R⁹, includes, for example, C₁₋₂₀ acyl groups such as formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, ethylcarbonyl, propylcarbonyl,tert-propylcarbonyl), C₁₋₆ alkoxy-carbonyls (e.g., methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,naphthoyl), C₆₋₁₄ aryloxy-carbonyl (e.g., phenoxycarbonyl), C₇₋₁₅aralkyl-carbonyl (e.g., C₆₋₁₄ aryl-C₁₋₆ alkyl-carbonyl such asbenzylcarbonyl), C₇₋₁₉ aralkyloxy-carbonyl (e.g., C₆₋₁₄ aryl-C₁₋₆alkoxy-carbonyl such as benzyloxycarbonyl), C₂₋₄ alkenyl-carbonyl (e.g.,2-propenylcarbonyl), tricyclic C₉₋₁₀ bridged hydrocarbon-carbonyl (e.g.,adamantylcarbonyl), etc.

[0131] Substituents in the acyl group which may be substituted areexemplified by the same groups as those mentioned to exemplifysubstituents in the above-described hydrocarbon group which may besubstituted.

[0132] In the above formulas, the heterocyclic group or the heterocyclicgroup in the heterocyclic group which may be substituted includes, forexample, 5- to 8-membered heterocyclic groups containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, nitrogen atoms etc., inaddition to carbon atoms, bicyclic or tricyclic condensed heterocyclicgroups resulting from condensation of 2 or 3 of such heterocyclicgroups, whether identical or not, and bicyclic or tricyclic condensedheterocyclic groups resulting from condensation of such a heterocyclicgroup and 1 or 2 benzene rings.

[0133] Examples of the heterocyclic group include, for example, (1)5-membered heterocyclic groups containing 1 to 4 hetero atoms selectedfrom oxygen atoms, sulfur atoms, nitrogen atoms etc., in addition tocarbon atoms, such as thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl,thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl,isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, triazinyl, triazolidinyl, and 1H- or2H-tetrazolyl; and (2) 6-membered heterocyclic groups containing 1 to 4hetero atoms selected from oxygen atoms, sulfur atoms, nitrogen atomsetc., in addition to carbon atoms, such as pyridyl, pyrimidinyl,thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, piperidinyl,pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl,piperazinyl, triazinyl, oxatriazinyl, pyridazinyl and pyrazinyl. (3)Bicyclic or tricyclic condensed heterocyclic groups include bicyclic ortricyclic condensed heterocyclic groups containing 1 to 4 hetero atomsselected from oxygen atoms, sulfur atoms, nitrogen atoms etc., inaddition to carbon atoms, such as benzofuryl, benzothiazolyl,benzoxazolyl, tetrazolo[1,5-bipyridazinyl, triazolo[4,5-b]pyridazinyl,benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, indolizinyl, indolyl, quinolizinyl,1,8-naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl,phenothiazinyl and phenoxazinyl.

[0134] Examples of substituents of the heterocyclic group which may besubstituted include, for example (1) C₁₋₆ alkyl, (2) C₂₋₆ alkenyl, (3)C₂₋₆ alkynyl, (4) C₃₋₆ cycloalkyl, (5) C₅₋₇ cycloalkenyl, (6) C₇₋₁₁aralky (C₆₋₁₀ aryl-C₁₋₅ alkyl such as benzyl and phenethyl, preferablybenzyl), (7) C₆₋₁₄ aryl (phenyl, naphthyl, anthryl, phenanthryl,acenaphtyl, anthracenyl, etc., preferably phenyl), (8) C₁₋₆ alkoxy, (9)C₆₋₁₄ aryloxy (e.g., phenoxy), (10) C₁₋₆ alkanoyl (e.g., formyl, acetyl,propionyl, n-butyryl, iso-butyryl), (11) C₆₋₁₄ arylcarbonyl (e.g.,benzoyl), (12) C₁₋₆ alkanoloxy (e.g., formyloxy, acetyloxy,propionyloxy, n-butylyloxy, iso-butylyloxy), (13) C₆₋₁₄ aryl-carbonyloxy(e.g., benzoy-loxy), (14) carboxy, (15) C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl), (16)carbamoyl, (17) N-mono-C₁₋₄ alkylcarbamoyl (e.g., N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl), (18) N,N-di-C₁₋₄ alkylcarbamoyl (e.g.,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-dibutylcarbamoyl), (19) 3- to 6-membered cyclic aminocarbonyl (e.g.,1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl),(20) halogen, (21) mono-, di- or tri-halogeno-C₁₋₄ alkyl (e.g.,chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl), (22)oxo, (23) amidino, (24) imino, (25) amino, (26) mono- or di-C₁₋₄alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino,butylamino, dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino), (27) 3- to 6-membered cyclic aminowhich may contain 1 to 3 hetero atoms selected from oxygen atoms, sulfuratoms, nitrogen atoms etc., in addition to carbon atoms and a nitrogenatom (e.g., aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino,dihydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl), (28) C₁₋₆alkanoylamino (e.g., formamido, acetamido, trifluoroacetamido,propionylamido, butyrylamido, isobutyrylamido), (29) benzamido, (30)carbamoylamino, (31) N—C₁₋₄ alkylcarbamoylamino (e.g.,N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino,N-isopropylcarbamoylamino, N-butylcarbamoylamino), (32) N,N-di-C₁₋₄alkylcarbamoylamino (e.g., N,N-dmethylcarbamoylamino,N,N-diethylcarbamoylamino, N,N-dipropylcarbamoylamino,N,N-dibutylcarbamoylamino), (33) C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy), (34) —B(OH)₂, (35) hydroxy, (36) epoxy(—O—), (37) nitro, (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino,(42) phosphono, (43) sulfamoyl, (44) C₁₋₆ alkylsulfamoyl (e.g.,N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfanoyl, N-butylsulfamoyl), (45) di-C₁₋₆ alkylsulfamoyl(e.g., N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl), (46) C₁₋₆ alkylthio (e.g.,methylthio, ethylthio, propylthio, isopropylthio, n-butylthio,sec-butylthio, tert-butylthio), (47) phenylthio, (48) C₁₋₆ alkylsulfinyle.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl),(49) phenylsulfinyl, (50) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl, propylsulfonyl, butylsulfonyl), and (51) phenylsulfonyl.

[0135] The number of substituents which may substitute the heterocyclicgroup is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

[0136] The heterocyclic group in the heterocyclic group having a bond ina carbon atom thereof which may be substituted is exemplified by 5- to8-membered heterocyclic groups containing 1 to 4 hetero atoms selectedfrom oxygen atoms, sulfur atoms, nitrogen atoms etc., in addition tocarbon atoms, bicyclic or tricyclic condensed heterocyclic groupsresulting from condensation of 2 or 3 of such heterocyclic groups,whether identical or not, and bicyclic or tricyclic condensedheterocyclic groups resulting from condensation of such a heterocyclicgroup and 1 or 2 benzene rings, which condensed heterocyclic groups havea bond in a constituent carbon atom thereof.

[0137] Examples of the heterocyclic group having a bond in a carbon atomthereof include, for example, (1) 5-membered heterocyclic groupscontaining 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms,nitrogen atoms etc., in addition to carbon atoms, such as thienyl (e.g.,2- or 3-thienyl), furyl (e.g., 2- or 3-furyl), pyrrolyl (e.g., 2- or3-pyrrolyl), oxazolyl (e.g., 2-, 4- or 5-oxazolyl), thiazolyl (e.g., 2-,4- or 5-thiazolyl), pyrazolyl (e.g., 3-, 4- or 5-pyrazolyl),pyrrolidinyl (e.g., 2- or 3-pyrrolidinyl), imidazolyl (e.g., 2-, 4- or5-imidazolyl), imidazolinyl (e.g., 2-imidazolinyl, 2-imidazolidinyl),isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl), isothiazolyl (e.g., 3-, 4- or5-isothiazolyl), oxadiazolyl [e.g., 3- or 5-(1,2,4-oxadiazolyl), 2-, 5-or 6-(1,3,4-oxadiazolyl)], thiadiazolyl [e.g., 3- or5-(1,2,4-thiadiazolyl, 2- or 5-(1,3,4-thiadiazolyl), 4- or5-(1,2,3-thiadiazolyl), 3- or 4-(1,2,5-thiadiazolyl)], and triazolyl(e.g., 2- or 5-(1,2,3-triazolyl), 3- or 5-(1,2,4-triazolyl)], tetrazolyl[e.g., 5-(1H- or 2H-tetrazolyl)]; (2) 6-membered heterocyclic groupscontaining 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms,nitrogen atoms etc., in addition to carbon atoms, such as pyridyl (e.g.,2-, 3- or 4-pyridyl), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl),thiomorpholinyl (e.g., 2- or 3-thiomorpholinyl), morpholinyl (e.g., 2-or 3-morpholinyl), triazinyl (e.g., 3- or 6-triazinyl), piperidinyl(e.g., 2-, 3- or 4-piperidinyl), pyranyl (e.g., 2- or 3-pyranyl),thiopyranyl (e.g., 2- or 3-thiopyranyl), oxazinyl [e.g., 2-or3-(1,4-oxazinyl)], thiazinyl [e.g., 2- or 3-(1,4-thiazinyl), 1- or4-(1,3-thiazinyl)], piperazinyl (e.g., 2- or 3-piperazinyl), triazinyl(e.g., 3- or 6-triazinyl), and pyridazinyl (e.g., 3- or 4-pyridazinyl);and (3) bicyclic or tricyclic condensed heterocyclic groups containing 1to 4 hetero atoms selected from oxygen atoms, sulfur atoms, nitrogenatoms etc., in addition to carbon atoms, and having a bond in aconstituent carbon atom thereof, such as benzofuryl, benzothiazolyl,benzoxazolyl, tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl,benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, indolizinyl, indolyl, quinolizinyl,1,8-naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl,phenothiazinyl and phenoxazinyl.

[0138] The substituents in the heterocyclic group having a bond in acarbon atom thereof which may be substituted is exemplified by the samesubstituents mentioned to exemplify the above-described heterocyclicgroup which may be substituted.

[0139] The cyclic amino group and the cyclic amino group in theabove-described cyclic amino group which may be substituted isexemplified by 5- to 7-membered nitrogen-containing cyclic groups whichmay have additional hetero atoms selected from oxygen atoms, sulfuratoms and nitrogen atoms. Examples of such groups include, for example,pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl,1,2,3-triazolidinyl, 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl,piperazinyl, azepinyl, hexamethyleneimino, oxazolidino, morpholino,thiazolidino and thiomorpholino. Preferred is 5- to 6-membered cyclicamino group, e.g., pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl,piperazinyl, morpholino and thiomorpholino.

[0140] The cyclic amino group may have 1 to 3 substituents at anypossible positions, such substituents including, for example, (1) C₁₋₆alkyl, (2) C₆₋₁₄ aryl, (3) C₇₋₁₀ aralkyl (phenyl-C₁₋₄ alkyl), (4)benzhydryl, (5) C₁₋₆ alkyl-carbonyl, (6) C₆₋₁₄ aryl-carbonyl, (7) C₁₋₆alkoxy-carbonyl, etc. Preferred is C₁₋₆ alkyl, more preferred is C₁₋₃alkyl.

[0141] The homocyclic group in the homocyclic group which may besubstituted is exemplified by 3- to 7-membered carbocyclic groups whichmay be condensed, such as C₆₋₁₀ aryl groups (e.g., phenyl, naphthyl),C₃₋₇ cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl) and C₃₋₇ cycloalkenyl gropus (e.g.,cyclopronyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl).

[0142] Such homocyclic groups may have 1 to 6, preferably 1 to 3, andmore preferably 1 to 2 substituents at any possible positions. Suchsubstituents include, for example, (1) C₁₋₁₅ alkyl which may besubstituted by 1 to 3, preferably 1 to 2 halogen(s), preferably C₁₋₆alkyl which may be substituted by halogen, (2) C₃₋₁₀ cycloalkyl, (3)C₂₋₁₀ alkenyl, (4) C₂₋₁₀ alkynyl, (5) C₃₋₁₀ cycloalkenyl, (6) C₆₋₁₀aryl, (7) C₇₋₂₀ aralkyl, (8) nitro, (9) hydroxy, (10) mercapto, (11)oxo, (12) thioxo, (13) cyano, (14) carbamoyl, (15) carboxy, (16) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl), (17) sulfo,(18) halogen, (19) C₁₋₆ alkoxy, (20) C₆₋₁₀ aryloxy (e.g., phenoxy), (21)C₁₋₆ acyloxy (e.g., C₁₋₆ alkanoyloxy such as acetoxy and propionyloxy),(22) C₁₋₆ alkylthio (e.g., methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, t-butylthio), (23) C₆₋₁₀ arylthio (e.g.,phenylthio), (24) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl), (25) C₆₋₁₀ arylsulfinyl (e.g., phenylsulfinyl), (26)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, (27) C₆₋₁₀arylsulfonyl (e.g., phenylsulfonyl), (28) amino, (29) C₁₋₆ acylamino(e.g., C₁₋₆ alkanoylamino such as acetylamino and propionylamino), (30)mono- or di-C₁₋₄ alkylamino (e.g., methylamino, ethylamino,n-propylamino, isopropylamino, n-butylamino, dimethylamino,diethylamino), (31) C₃₋₈ cycloalkylamino (e.g., cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino), (32) C₆₋₁₀arylamino (e.g., anilino), (33) C₁₋₆ alkanoyl (e.g., formyl, acetyl,hexanoyl), (34) C₆₋₁₀ aryl-carbonyl (e.g., benzoyl), and (35) 5- to6-membered heterocyclic groups containing 1 to 4 hetero atoms selectedfrom oxygen atom, sulfur atom, and nitrogen atom, in addition to carbonatoms [e.g., thienyl (e.g., 2- or 3-thienyl), furyl (e.g., 2- or3-furyl), pyrazolyl (e.g., 3-, 4- or 5-pyrazolyl), thiazolyl (e.g., 2-,4- or 5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),oxazolyl (e.g., 2-, 4- or 5-oxazolyl), isoxazolyl (e.g., 3-, 4- or5-isoxazolyl), imidazolyl (e.g., 2-, 4- or 5-imidazolyl), triazolyl(e.g., 1,2,3- or 1,2,4-triazolyl), tetrazolyl (e.g., 1H- or2H-tetrazolyl), pyridyl (e.g., 2-, 3- or 4-pyridyl), pyrimidyl (e.g.,2-, 4- or 5-pyrimidyl), pyridazinyl (e.g., 3- or 4-pyridazinyl),quinolyl, isoquinolyl, indolyl, etc.], and so forth.

[0143] The hydroxy group which may be substituted for R⁸ and R¹⁰includes a group of the formula: —OR¹³ wherein R¹³ is defined as above.

[0144] In the above formulas, R¹, R² and R³ each is preferably (i)hydrogen or (ii) the above-described group bound via a carbon atom, anitrogen atom or an oxygen atom. Preference is given to the case whereinR¹ is a C₁₋₁₅ alkyl group which may be substituted, a C₃₋₁₀ cycloalkylgroup which may be substituted, a C₂₋₁₀ alkenyl group which may besubstituted, a C₂₋₁₀ al yl group which may be substituted, a C₃₋₁₀cycloalkenyl group which may be substituted, a C₆₋₁₄ aryl group whichmay be substituted, a C₇₋₂₀ aralkyl group which may be substituted, aC₁₋₂₀ acyl group which may be substituted, a nitro group, a group of theformula: —NR¹⁰R¹¹ wherein R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon groupwhich may be substituted, a C₁₋₂₀ acyl group which may be substituted, ahydroxy group which may be substituted, a heterocyclic group which maybe substituted, or a group of the formula: —S(O)t-R¹² wherein t is aninteger from 0 to 2, and R¹² is hydrogen, a C₁₋₁₀ hydrocarbon groupwhich may be substituted or a heterocyclic group; R¹¹ is hydrogen or aC₁₋₁₀ hydrocarbon group; or R¹⁰ and R¹¹ may form, taken together withthe adjacent nitrogen atom, a cyclic amino group which may besubstituted, or a group of the formula: —O—R¹³ wherein R¹³ is hydrogenor a C₁₋₁₀ hydrocarbon group which may be substituted, a C₁₋₂₀ acylgroup which may be substituted, a C₁₋₂₀ alkylsulfonyl group which may besubstituted, a C₆₋₁₄ arylsulfonyl group which may be substituted or a 5-to 8-membered heterocyclic group (the same as the above-described “5- to8-membered heterocyclic group containing 1 to 4 hetero atoms selectedfrom oxygen atoms, sulfur atoms, nitrogen atoms etc., in addition tocarbon atoms”), and wherein at least one of R² and R³ is hydrogen, andthe other is the above group bound via a carbon atom, a nitrogen atom,or an oxygen atom, preferably R² and R³ are both hydrogen.

[0145] R¹ is preferably a C₁₋₁₀ alkyl group (preferably C₁₋₆ alkylgroup) which may be substituted by 1 to 3, preferably 1 hydroxy, a nitrogroup, an amino group, a group of the formula: —NR¹⁰R¹¹ wherein R¹⁰represents hydrogen; R¹¹ represents a C₁₋₆ alkyl-carbonyl group whichmay be substituted by 1 to 3, preferably 1 hydroxy, a C₁₋₆alkylamino-carbonyl group or a C₆₋₁₄ arylamino-carbonyl group), or agroup of the formula: —O—R¹³ wherein R¹³ represents hydrogen, a C₁₋₁₀alkyl group which may be substituted by 1 to 3, preferably 1 hydroxy, aC₁₋₆ alkyl-carbonyl which may be substituted by C₃₋₁₀ cycloalkyl or 1 to3, preferably 1 hydroxy, a C₁₋₆ alkylsulfonyl group, or a C₆₋₁₀arylsulfonyl group.

[0146] In the above formulas, R⁴ is preferably (1) a C₁₋₂₀ hydrocarbongroup which may be substituted, (2) a C₁₋₂₀ acyl group which may besubstituted, (3) a heterocyclic group having a bond in a carbon atomthereof which may be substituted, (4) a carboxy group which may beesterified or amidated, or (5) a cyano group. More preferably, R⁴ is aC₁₋₁₅ alkyl group which may be substituted, a C₃₋₁₀ cycloalkyl groupwhich may be substituted, a C₂₋₁₀ alkenyl group which may besubstituted, a C₂₋₁₀ alkynyl group which may be substituted, a C₃₋₁₀cycloalkenyl group which may be substituted, a C₆₋₁₄ aryl group whichmay be substituted or a C₇₋₂₀ aralkyl group which may be substituted.Still more preferred is a C₁₋₆ alkyl group which may be substituted suchas an aminoalkyl group which may be substituted. A preferred example ofR⁴ is the formula: —(CH₂)n-NR¹⁰R¹¹ wherein n is an integer from 1 to 3;R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon group which may be substituted, aC₁₋₂₀ acyl group which may be substituted, a hydroxy group which may besubstituted (group of the formula: —O—R¹³ above), a heterocyclic groupwhich may be substituted, or a group of the formula: —S(O)t-R¹² whereint is an integer from 0 to 2; R¹² is hydrogen or a C₁₋₁₀ hydrocarbongroup which may be substituted; R¹¹ is hydrogen or a C₁₋₁₀ hydrocarbongroup; or R¹⁰ and R¹¹ may form, taken together with the adjacentnitrogen atom, a cyclic amino group which may be substituted. R⁴ is morepreferably a halogen atom, a hydroxy group which may be substituted byC₁₋₂₀ acyl, or a C₁₋₃ alkyl group which may be substituted by aminogroup which may be substituted by C₁₁ alkyl and/or C₆₋₁₄ aryl-C₁₋₁₀alkyl. R⁴ is most preferably N—C₁₋₆ alkyl-N-benzylaminomethyl.

[0147] In the above formulas, R⁵ is preferably hydrogen or a C₁₋₁₅ alkylgroup which may be substituted, a C₃₋₁₀ cycloalkyl group which may besubstituted, a C₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀alkynyl group which may be substituted, a C₃₋₁₀ cycloalkenyl group whichmay be substituted, a C₆₋₁₄ aryl group which may be substituted, a C₇₋₂₀aralkyl group which may be substituted, a C₁₋₂₀ acyl group which may besubstituted, a carboxy group which maybe esterified or amidated, or agroup of the formula: —O—R¹³ wherein R¹³ is hydrogen, a C₁₋₁₅ alkylgroup which may be substituted, a C₃₋₁₀ cycloalkyl group which may besubstituted, a C₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀alkynyl group which may be substituted, a C₃₋₁₀ cycloalkenyl group whichmay be substituted, a C₆₋₁₄ aryl group which may be substituted, a C₇₋₂₀aralkyl group which may be substituted, a C₁₋₂₀ acyl group which may besubstituted, a C₁₋₂₀ alkylsulfonyl group which may be substituted, aC₆₋₁₄ arylsulfonyl group which may be substituted or a heterocyclicgroup which may be substituted. Preferred examples of R⁵ includehydrogen, a C₁₋₁₅ alkyl group which may be substituted by 1 to 3,preferably 1 C₆₋₁₄ aryl or C₁₋₆ alkoxy, or a C₁₋₆ alkyl-carbonyl, C₁₋₆alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl), C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl), C₇₋₁₅ aralkyl-carbonyl (e.g.,benzylcarbonyl), C₇₋₁₉ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl),N—C₁₋₁₀ alkyl-N—(C₁₋₁₀ alkoxy)amino-carbonyl (e.g.,N-methyl-N-methoxyamino-carbonyl), C₁₋₁₅ alkyloxy and C₁₋₂₀ arylsulfonylgroup which may be substituted by 1 to 3, preferably 1 hydroxy. Morepreferred is (1) a C₁₋₆ alkoxy-carbonyl group, (2) a C₆₋₁₀ aryl groupwhich may be substituted by halogen or C₁₋₆ alkoxy, or (3) a phenyl-C₁₋₃alkyl group.

[0148] In the above formulas, R⁶ is preferably hydrogen, a C₁₋₁₅ alkylgroup which may be substituted, a C₃₋₁₀ cycloalkyl group which may besubstituted, a C₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀alkynyl group which may be substituted, a C₃₋₁₀ cycloalkenyl group whichmay be substituted, a C₆₋₁₄ aryl group which may be substituted or aC₇₋₂₀ aralkyl group which may be substituted. More preferably, R⁶ ishydrogen or a C₁₋₁₀ alkyl group. Still more preferably, R⁶ is hydrogenor a C₁₋₆ alkyl group.

[0149] In the above formulas, R⁷ is a homocylic group or heterocyclicgroup which may be substituted, preferably a C₆₋₁₄ aryl group which maybe substituted. More preferably, R⁷ is a phenyl group which may besubstituted by 1 to 3, preferably 1 to 2 halogen or C₁₋₆ alkoxy.Particularly preferred is a phenyl group which may be substituted by 1to 2 halogen(s).

[0150] In the above formula (I), m is 0 to 3, preferably 0 to 2, andmore preferably 0 or 1.

[0151] In the above formula, n is an integer from 1 to 3, preferably 1or 2, and more preferably 1.

[0152] In the above formula or the following formula, each of X, X¹ andX² represents a leaving group (e.g., halogen atoms, mesyl, tosyl),preferably halogen atoms (e.g., chlorine, bromine).

[0153] In the following formula, X³ represents a leaving group, forexample, N,N-di-C₁₋₄ alkylamino (e.g., dimethylamino), C₁₋₁₀ alkoxy(e.g., methoxy, ethoxy), C₁₋₁₀ acyl (e.g., C₁₋₁₀ alkanoyl such asacetyl), C₁₋₁₀ acyloxy (e.g., C₁₋₁₀ alkanoyloxy such as acetoxy),halogen atoms (e.g., chlorine, bromine), mesyl, tosyl, etc. Preferably,X³ is N,N-di-C₁₋₄ alkylamino (e.g., dimethylamino) and C₁₋₁₀ alkoxy(e.g., methoxy, ethoxy).

[0154] In the above formula (I), one of A and D represents a nitrogenatom and the other represents a carbon atom, or both represent anitrogen atom; B represents a nitrogen atom or a carbon atom. Compoundsrepresented by the formula (I) are therefore exemplified by compoundsrepresented by the following formulas:

[0155] wherein the symbols have the same definitions as those givenabove, preferably compounds represented by the formula (a), (b), (c),(d), (e) or (g).

[0156] Among others, preferred is a compound of formula (I) wherein B isa nitrogen atom, more preferred is a compound represented by the formula(c) or (e), and most preferred is a compound represented by the formula(e).

[0157] In compound (I), preferred is a compound of the formula:

[0158] wherein each symbol is as defined above, or a salt thereof. Amongothers, preferred is a compound wherein R¹ is (1) an amino group whichmay be substituted by (i) carbamoyl which may be substituted by C₁₋₆alkyl or C₁₋₆ alkoxy, or (ii) C₁₋₆ alkyl-carbonyl, or (2) a C₁₋₆ alkoxygroup which may be substituted by C₃₋₆ cycloalkyl;

[0159] R⁴ is a N—C₁₋₆ alkyl-N-benzylaminomethyl group R⁵ is (1) a C₁₋₆alkoxy-carbonyl group, (2) a C₆₋₁₀ aryl group which may be substitutedby halogen or C₁₋₆ alkoxy, or (3) a phenyl-C₁₋₃ alkyl group; and

[0160] R⁶ is hydrogen.

[0161] Another preferable example is a compound or a salt thereof,wherein R¹ is (1) a nitro group, (2) an amino group which may besubstituted by 1 or 2 substituents selected from the group consisting of(i) C₁₋₆ alkyl which may be substituted by hydroxy, (ii) C₁₋₆alkyl-carbonyl which may be substituted by hydroxy, halogen or thienyl,(iii) C₆₋₁₀ aryl-carbonyl which may be substituted by C₁₋₆ alkyl, C₁₋₆alkoxy or halogen, (iv) C₃₋₆ cycloalkyl-carbonyl, (v) C₂₋₄alkenyl-carbonyl, (vi) C₁₋₆ alkoxy-carbonyl, (vii) C₁₋₆alkylamino-carbonyl, (viii) C₁₋₆ alkoxyamino-carbonyl, (ix)phenylaminocarbonyl, (x) an isoxazolylcarbonyl, thienylcarbonyl,thiazolylcarbonyl, pyrazolylcarbonyl or furylcarbonyl group which may besubstituted by 1 or 2 substituents selected from the group consisting ofC₁₋₆ alkyl, nitro and C₁₋₆ alkoxy, (xi) pyridylcarbonyl, (xii) C₁₋₆alkylsulfonyl, (xiii) thienylsulfonyl and (xiv) phenylsulfonyl which maybe substituted by C₁₋₆ alkyl, (3) a pyrrolyl group or (4) a hydroxygroup which may be substituted by C₁₋₆ alkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylor C₁₋₆ alkyl-carbonyl;

[0162] R⁴ is a C₁₋₆ alkyl group which may be substituted by 1 or 2substituents selected from the group consisting of (1) halogen, (2)hydroxy and (3) amino which may be substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₃ alkyl anddi-C₁₋₆ alkylamino-C₁₋₃ alkyl;

[0163] R⁵ is (1) halogen, (2) a phenyl group which may be substituted byhalogen or C₁₋₆ alkyl, or (3) a carbonyl group substituted by (i) C₁₋₆alkyl, (ii) amino substituted by C₁₋₆ alkyl and C₁₋₆ alkoxy or (iii)C₁₋₆ alkoxy; and

[0164] R⁶ is hydrogen or a C₁₋₃ alkyl group.

[0165] As compound (I), concretely mentioned are8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(methoxyaminocarbonylamino)phenyll-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester, or salts thereof.

[0166] The compound of the present invention can be produced by themethods described below or analogous thereto, per se known methods suchas methods described in WO 95/28405, or combination thereof.

[0167] wherein the symbols have the same definitions as those givenabove.

[0168] 2-Aminopyrimidine derivative (i) is dissolved in an appropriateinert solvent (e.g., ethers such as ethyl ether, dioxane,dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such asbenzene and toluene, amides such as dimethylformamide anddimethylacetamide, alcohols such as methanol and ethanol,dichloromethane, acetone, etc.), and then, 1 eq. to slight excess (about1 to 3 mol) of α-haloketone derivative (ii) is added, followed bystirring at about 0 to 40° C., for about 1 to 4 hours, to yield cyclizedderivative (iii). This (iii) is added little by little to an appropriatesolvent (e.g., acetic acid), followed by addition of an appropriatemetal (e.g., zinc powder) during stirring at about 0 to 80° C., to yieldcondensed derivative (iv). The aminopyrimidine derivative can beproduced by a per se known methods, for example, methods described inthe Journal of the Indian Chemical Society, 2, 61-70 (1925).

[0169] The derivative (iv) or its tautomer (iv′) is dissolved in anappropriate inert solvent (e.g., dimethylformamide, dichloromethane,tetrahydrofuran, ethyl ether, dioxane and acetone), and then 1 eq. toslight excess (about 1 to 3 mol) of a base (e.g., potassium carbonate,triethylamine and sodium hydride) and 1 eq. to excess of compound (v)(e.g., halogenated alkyl derivatives such as benzyl iodide) are added,followed by stirring at about 0 to 80° C. Desired compound (e) can bethus produced.

[0170] This reaction is also carried out in the presence of a base. Thebase is exemplified by inorganic bases such as sodium carbonate, sodiumhydrogen carbonate, potassium carbonate, potassium hydrogen carbonate,sodium hydroxide, potassium hydroxide and thallium hydroxide, andorganic bases such as triethylamine. Reaction temperature is normallyabout 0 to 150° C., preferably about 15 to 25° C. (about 20° C.).Reaction time is about 1 to 12 hours.

[0171] wherein the symbols have the same definitions as those givenabove.

[0172] Conversion of 3-position Substituent on ImidazopyrimidineBackbone

[0173] Compound (e1) is stirred with N-bromosuccinimide (NBS) in asolvent that does not affect the reaction (e.g., halogenatedhydrocarbons such as carbon tetrachloride and chloroform) in thepresence of α,α′-azobisisobutyronitrile (AIBN) at 30 to 100° C. for 0.5to 6 hours, to yield compound (e2).

[0174] By reacting compound (e2) or a salt thereof with an amine(R⁸R⁹NH) in a nearly equimolar amount, compound (e3) of the presentinvention or a salt thereof is produced. This reaction is carried out inan appropriate inert solvent. The appropriate solvent is exemplified byamides such as dimethylformamide and dimethylacetamide, nitriles such asacetonitrile, alcohols such as ethanol, ethers such as dimethoxyethane,tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbonssuch as dichloromethane, nitriles such as acetonitrile, ketones such asacetone, and esters such as ethyl acetate. This reaction is carried outin the presence of a non-nucleophilic base. The base is exemplified bytertiary organic amines (e.g., triethylamine, trimethylamine,diisopropylethylamine, N-methylmorpholine). Reaction temperature isnormally about 10 to 100° C. Reaction time is about 1 to 10 hours.Preferably, this reaction is carried out during stirring. Compound (e3)can be thus produced.

[0175] wherein R^(a) represents a C₁₋₆ alkyl group; the other symbolshave the same definitions as those given above.

[0176] In compound (I), compound (e) or (c) or a salt thereof can beproduced by reacting 2-aminoimidazole derivative (vi-a) or2-aminopyrrole derivative (vi-b) or a salt thereof with acrylic acidcompound (vii) such as an ethoxymethylenecarboxylic acid derivative,then reacting with compound (v).

[0177] In this reaction, acrylic acid compound (vii) is used at 1 to 3mol per mol of compound (vi-a) or (vi-b) or a salt thereof. The reactionis carried out in the absence of a solvent or in an appropriate inertsolvent. The appropriate solvent is exemplified by ethers such as ethylether, dioxane, dimethoxyethane and tetrahydrofuran, aromatichydrocarbons such as benzene and toluene, amides such asdimethylformamide and dimethylacetamide, and alcohols such as methanoland ethanol. This reaction is also carried out in the presence of abase. The base is exemplified by inorganic bases such as sodiumcarbonate, sodium hydrogen carbonate, potassium carbonate, potassiumhydrogen carbonate, sodium hydroxide, potassium hydroxide and thalliumhydroxide, and organic bases such as triethylamine. Reaction temperatureis normally about 0 to 150° C., preferably about 15 to 25° C. Reactiontime is about 1 to 12 hours. To produce the desired condensed ringcompound, there may be added an additional process wherein the adductbetween 2-aminoimidazole derivative (vi-a) or 2-aminopyrrole derivative(vi-b) or a salt thereof and acrylic acid compound (vii) is onceisolated and reacted with compound (v) in an appropriate inert solvent.The appropriate solvent is exemplified by polyphosphoric acid (PPA),polyphosphoric acid ester (PPE), diphenyl ether, etc.

[0178] Compounds (e) and (c) thus produced can be subjected toalkylation or amino group introducing reaction shown for theabove-described production methods, production methods 1 and 2.

[0179] wherein R^(g) represents a protecting group (e.g.,benzyloxymethyl); R^(b) represents a C₁₋₆ alkyl group; the other symbolshave the same definitions as those given above.

[0180] Compound (f1) of the present invention or a salt thereof can beproduced, using aminopyrrole compound (4b) as obtained by reactingamidine acetate ester compound (4a) or a salt thereof with carbonylcompound (1b) as the starting material. The aminopyrrole compound can beproduced by a per se known method, for example, Synthesis, p. 272(1987).

[0181] In this reaction, 1 mol of compound (4a) or a salt thereof isreacted with about 1 to 3 mol of carbonyl compound (1b) in anappropriate inert solvent (e.g., ethers such as ethyl ether, dioxane,dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such asbenzene and toluene, amides such as dimethylformamide anddimethylacetamide, alcohols such as methanol and ethanol, esters such asethyl acetate ester), to yield aminopyrrole compound (4b). Reactiontemperature is normally about 15 to 150° C., preferably room temperature(about 15 to 25° C.). Reaction time is about 1 to 12 hours.

[0182] The aminopyrrole compound (4b) is dissolved in an appropriateinert solvent (e.g., amides such as dimethylformamide anddimethylacetamide, nitrites such as acetonitrile, alcohols such asethanol, ethers such as dimethoxyethane, tetrahydrofuran, dioxane anddimethoxyethane, halogenated hydrocarbons such as dichloromethane,nitrites such as acetonitrile, ketones such as acetone, esters such asethyl acetate), after which it is reacted with compound (4c) (e.g.,chloromethyl benzyl ether) in the presence of a base (e.g., potassiumcarbonate, aqueous solution of sodium hydroxide, triethylamine, sodiumhydride), to yield compound (4d). Reaction temperature is normally about15 to 150° C., preferably room temperature (about 15 to 25° C.).Reaction time is about 1 to 12 hours.

[0183] Compound (4d) is dissolved in an appropriate inert solvent (e.g.,dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether,dioxane, acetone), and then, 1 eq. to slight excess (about 1 to 3 mol)of base (e.g., potassium carbonate, triethylamine, sodium hydride) and 1eq. to excess (about 3 mol) of halogenated alkyl compound (4e) (e.g.,benzyl bromide) are added, followed by stirring at about 0 to 80° C. forabout 1 to 24 hours, to yield compound (4f).

[0184] Compound (4f) is dissolved in an appropriate inert solvent (e.g.,dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether,dioxane, acetone), and then, about 1 eq. to slight excess (about 1 to 3mol) of base (e.g., potassium carbonate, triethylamine, sodium hydride)and about 1 eq. to excess (about 3 mol) of halogenated propionic acidester compound (4g) (e.g., 3-chloropropionic acid ethyl ester) areadded, followed by stirring at about 0 to 80° C. for about 1 to 24hours, to yield compound (4h).

[0185] Compound (4h) is dissolved in an appropriate inert solvent (e.g.,dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether,dioxane, acetone), and then, about 1 eq. to slight excess (about 1 to 3mol) of base (e.g., bistrimethylsilylamide sodium salt) is added,followed by stirring at about 0 to 80° C. for about 1 to 24 hours, toyield compound (4i).

[0186] Compound (4i) is dissolved in an appropriate inert solvent (e.g.,ethanol, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane,acetone), and then, about 1 eq. to slight excess (about 1 to 3 mol) ofbase (e.g., potassium acetate, triethylamine, sodium hydride) and 1 eq.to excess (about 3 to 5 mol) of oxidant (e.g., iodine, bromine) areadded, followed by stirring at about 0 to 80° C. for about 1 to 12hours, to yield compound (4j).

[0187] Compound (4j) is dissolved in an inert solvent (e.g.,dichloromethane, tetrahydrofuran), and then, about 1 eq. to slightexcess (about 1 to 3 mol) of copper iodide and 1 to 10 eq. of Grignardreagent R⁶MgX are added, followed by stirring at about 0 to 80° C. forabout 1 to 12 hours, to yield a 1,4-adduct compound.

[0188] The adduct compound is dissolved in an inert solvent (e.g.,tetrahydrofuran, dimethylformamide, dioxane, toluene, benzene), andthen, about 1 eq. to slight excess (about 1 to 3 mol) of base (e.g.,sodium hydroxide, sodium hydride) and 1 eq. to slight excess (about 1 to3 mol) of oxidant (e.g., iodine, bromine) are added, followed bystirring at about 0 to 80° C. for about 1 to 12 hours, to yield compound(4k).

[0189] By subjecting the compound (4k) to a per se known deprotection(e.g., catalytic reduction), compound (f1) or a salt thereof can beproduced.

[0190] wherein R^(g) represents a protecting group (e.g.,benzyloxymethyl group); R^(c) represents a group bound via a carbon atombut other than a carboxylic acid ester group (e.g., C₁₋₁₀ alkyl groups,C₁₋₂₀ acyl groups); the other symbols have the same definitions as thosegiven above.

[0191] Compound (4k) is dissolved in an appropriate inert solvent (e.g.,ethanol, methanol, dimethylformamide), and then a reducing agent (e.g.,sodium borohydride, dibutylaluminum hydride) in excess is added,followed by stirring at about 0 to 60° C. for about 1 to 12 hours, toyield compound (4m).

[0192] Next, 1 mol of compound (4m) is reacted with about 1 to 3 mol ofhalogenated carbon compound R^(c)X (e.g., halogenated C₁₋₂₀ acyl,halogenated C₁₋₁₀ alkyl) in an appropriate inert solvent (e.g., etherssuch as ethyl ether, dioxane, dimethoxyethane and tetrahydrofuran,aromatic hydrocarbons such as benzene and toluene, amides such asdimethylformamide and dimethylacetamide, esters such as ethyl acetateester) in the presence of 1 eq. to slight excess (about 1 to 3 mol) ofbase (e.g., potassium carbonate, triethylamine, sodium hydride) to yieldcompound (4n). Reaction temperature is normally about 15 to 150° C.,preferably room temperature (about 15 to 25° C.). Reaction time is about1 to 12 hours.

[0193] The compound (4n) is dissolved in an appropriate inert solvent(e.g., ethanol, tetrahydrofuran, ethyl ether, dioxane), and then, anaqueous solution of alkali (e.g., aqueous solution of potassiumhydroxide, sodium hydroxide etc.) in excess is added, followed bystirring at about 15 to 150° C. for about 1 to 24 hours, to yieldcompound (4p).

[0194] The compound (4p) is dissolved in an appropriate inert solvent(e.g., tetrahydrofuran, dimethylformamide, dioxane, toluene, benzene),and then, an acid (e.g., hydrochloric acid, tosic acid, trifluoroaceticacid) is added, followed by stirring at about 15 to 150° C. for about 1to 24 hours, to yield decarboxylated compound (4q).

[0195] The compound (4q) is dissolved in an appropriate inert solvent(e.g., tetrahydrofuran, dimethylformamide, dioxane, toluene, benzene),and then, about 1 eq. to slight excess of base (e.g., sodium hydroxide,sodium hydride) and 1 eq. to slight excess (about 1 to 3 mol) of oxidant(e.g., iodine, bromine) are added, followed by stirring at about 0 to80° C. for about 1 to 12 hours, to yield compound (4r).

[0196] By subjecting the compound (4r) to a per se known deprotection(e.g., catalytic reduction), compound (f2) or a salt thereof can beproduced.

[0197] wherein R^(g) represents a protecting group (e.g.,benzyloxymethyl); R^(d) represents C₁₋₂₀ acyl; the other symbols havethe same definitions as those given above.

[0198] Compound (4r) is dissolved in an appropriate inert solvent (e.g.,dichloromethane, dimethylformamide), and then, about 1 eq. to slightexcess (about 1 to 3 mol) of oxidant (e.g., metachloroperbenzoic acid)is added, followed by stirring at about 0 to 100° C. for about 1 to 24hours, to yield a rearrangement product. Thus obtained rearrangementproduct is dissolved in an appropriate inert solvent (e.g.,tetrahydrofuran, ethanol, dimethylformamide), and then, great excess(about 3 to 5 mol) of aqueous solution of alkali (e.g., aqueous solutionof potassium hydroxide, sodium hydroxide etc.) is added, followed bystirring at about 15 to 150° C. for about 1 to 12 hours, to yieldcompound (4s).

[0199] The compound (4s) is dissolved in an appropriate inert solvent(e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dioxane,toluene, benzene), and then, about 1 eq. to slight excess (about 1 to 3mol) of base (e.g., sodium hydride, potassium carbonate) and about 1 eq.to slight excess (about 1 to 3 mol) of halogenated compound R¹³X (e.g.,halogenated C₁₋₂₀ acyl, halogenated C₁₋₂₀ alkylsulfonyl, halogenatedC₁₋₁₅ alkyl) are added, followed by stirring at about 0 to 80° C. forabout 1 to 24 hours, after which a per se known deprotection (e.g.,catalytic reduction) is carried out, to yield compound (f3) or a saltthereof.

[0200] wherein R^(g) represents a protecting group (e.g.,benzyloxymethyl); R^(e) represents C₆₋₁₄ aryl; the other symbols havethe same definitions as those given above

[0201] Compound (4s) is dissolved in an appropriate inert solvent (e.g.,tetrahydrofuran, dichloromethane, dimethylformamide), and then, about 1eq. to slight excess (about 1 to 3 mol) of base (e.g., sodium hydride,potassium carbonate) and about 1 eq. to slight excess (about 1 to 3 mol)of trifluoroacetic anhydride are added, followed by stirring at about 0to 80° C. for about 1 to 12 hours, to yield compound (4t).

[0202] Compound (4t) is dissolved in an appropriate inert solvent (e.g.,tetrahydrofuran, dimethoxyethane), and then, about 1 to 10 eq. ofaqueous solution of alkali (e.g., aqueous solution of potassiumcarbonate, sodium carbonate etc.), 1 eq. to slight excess (about 1 to 3mol) of R^(e)B(OH)₂ (e.g., C₆₋₁₄ arylboric acid compounds such asphenylboric acid), and 0.1 to 0.5 eq. of tetrakistriphenylphosphinepalladium [(Ph₃P)₄] are added, followed by stirring at about 15 to 150°C. for about 1 to 24 hours, after which a per se known deprotection(e.g., catalytic reduction) is carried out, to yield compound (f4) or asalt thereof.

[0203] wherein X represents a halogen atom; the other symbols have thesame definitions as those given above.

[0204] Compound (g) of the present invention or a salt thereof can beproduced, using compound (f) or a salt thereof as the starting material.

[0205] In this reaction, 1 mol of compound (f) or a salt thereof isreacted with about 1 to 10 mol of zinc or iron and about 1 to 10 mol ofa strong acid (e.g., hydrochloric acid, sulfuric acid) in an appropriateinert solvent (e.g., organic acids such as acetic acid, alcohols such asmethanol and ethanol). Reaction temperature is normally about 15 to 150°C., preferably room temperature (about 15 to 25° C.). Reaction time isabout 1 to 12 hours. Compound (5a) obtained is dissolved in anappropriate inert solvent (e.g., dimethylformamide, dichloromethane,tetrahydrofuran, ethyl ether, dioxane, acetone), and then, ahalogenating agent (e.g., sodium hypochlorite, t-butyl hypochlorite,trichloroisocyanuric acid) is added, followed by stirring at about 15 to150° C. Compound (5b) obtained is dissolved in an appropriate inertsolvent (e.g., dimethylformamide, dichloromethane, tetrahydrofuran,ethyl ether, dioxane, acetone, ethanol), and then, about 1 eq. to slightexcess (about 1 to 3 mol) of base (e.g., potassium carbonate,triethylamine, sodium hydride) is added, followed by stirring at about 0to 80° C., to yield compound (g) or a salt thereof.

[0206] Production Method 6

[0207] Other methods:

[0208] Substituents in groups in the compound of the present inventioncan be converted to other substituents by per se known methods in commonuse. Examples of this method are given below.

[0209] (i) The nitro group as a substituent can be converted to theamino group. For example, the starting compound is dissolved in anappropriate solvent (e.g., methanol, ethanol), after which (a)palladium-carbon is added and a reaction is carried out in a hydrogenstream at about 15 to 25° C. for 1 to 12 hours, or (b) iron powder andhydrochloric acid are added to the above solution and a reaction iscarried out at about 15 to 25° C. for 1 to 12 hours.

[0210] (ii) The amino group as a substituent can be converted to anacylated amino group. For example, the starting compound is dissolved inan appropriate solvent (e.g., tetrahydrofuran, dimethyl sulfoxide), andthen, potassium carbonate and the bases pyridine and triethylamine areadded, then, an acid anhydride or an acid halide is added. The mixtureis reacted during stirring at about 15 to 25° C. for 1 to 10 hours.

[0211] (iii) A compound having the amino group can be converted to analkenylamino compound. For example, the starting compound is dissolvedin an appropriate solvent (e.g., acetic acid, dimethylformamide,dichloromethane, tetrahydrofuran, dioxane, acetonitrile), and, adiazotizing agent (e.g., sodium nitrate, isoamyl nitrate) is added, andthen a palladium catalyst [e.g., bis(dibenzylideneacetone) palladium)]and 1 eq. to slight excess of alkenyl derivative are added and areaction is carried out at about 15 to 80° C. for 1 to 12 hours.

[0212] (iv) A carbon atom can be introduced to the amino group. Forexample, the starting compound is dissolved in an appropriate solvent(e.g., acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran,dioxane), and then, an acrylic acid derivative or an oxirane derivative(e.g., epoxide compounds) is added and a reaction is carried out duringstirring at 0 to 80° C. for 6 to 24 hours.

[0213] (v) The formyl group as a substituent can be converted to themethyl group. For example, the starting compound is dissolved in anappropriate solvent (e.g., tetrahydrofuran), and then, an organic boranederivative (e.g., dimethyl sulfide borane) is added and a reaction iscarried out during refluxing at about 15 to 80° C. for several hours(e.g., 1 to 3 hours).

[0214] (vi) From the methoxy, another alkoxy can be produced. Forexample, the starting compound is dissolved in an appropriate solvent(e.g., dichloromethane), and then, 1 eq. to excess of Lewis acid (e.g.,aluminum chloride) and a thiol compound or a sulfide compound (e.g.,dimethyl sulfide) are added and a reaction is carried out at about 0 to20° C. for 1 to 10 hours. The hydroxy obtained is then dissolved in anappropriate solvent (e.g., dimethylformamide), and then, a base (e.g.,sodium hydroxide, potassium carbonate) and an alkyl halide are added anda reaction is carried out at about 15 to 25° C. for 1 to 12 hours.

[0215] (vii) From the methoxy, the acyloxy can be produced. For example,the starting compound is dissolved in an appropriate solvent (e.g.,dichloromethane), and then, 1 eq. to excess of Lewis acid (e.g.,aluminum chloride) and a thiol compound or a sulfide compound (e.g.,dimethyl sulfide) are added and a reaction is carried out at about 0 to20° C. for 1 to 10 hours. The hydroxy obtained is then dissolved in anappropriate solvent (e.g., dimethylformamide), and then a base (e.g.,sodium hydroxide, potassium carbonate) and an acyl halide are added anda reaction is carried out at about 15 to 25° C. for 1 to 12 hours.

[0216] (viii) The methoxy can be converted to an alkyne derivative. Forexample, the starting compound is dissolved in an appropriate solvent(e.g., dichloromethane), and then, 1 eq. to excess of Lewis acid (e.g.,aluminum chloride) and a thiol compound or a sulfide compound (e.g.,dimethyl sulfide) are added and a reaction is carried out at about 0 to20° C. for 1 to 10 hours. The hydroxy obtained is then dissolved in anappropriate solvent (e.g., dimethylformamide), and then, a base (e.g.,pyridine, triethylamine) and trifluoromethanesulfonic anhydride areadded and a reaction is carried out at about 15 to 25° C. for 1 to 12hours, to yield a triflate derivative. The triflate derivative obtainedis then dissolved in an appropriate solvent (e.g., piperidine,pyrrolidine), and then, an alkyne derivative (e.g., propargyl alcohol,3-butyn-1-ol) and a palladium compound as a catalyst [e.g.,tetrakdis(triphenylphosphine)palladium (0-valency) are added and areaction is carried out during refluxing for 1 to 6 hours.

[0217] (ix) An alkylthio compound can be converted to an alkylsulfinylcompound or an alkylsulfonyl compound. For example, the startingcompound is reacted with an oxidant (e.g., metachloroperbenzoic acid) inan appropriate solvent (e.g., dichloromethane). Provided thatsuperheating or the antioxidant is used in excess, an allylsulfonylcompound is obtained.

[0218] (x) The hydroxy group in the molecule can be substituted byvarious groups. The reaction is carried out in an appropriate solvent[e.g., dimethylformamide (DMF), acetonitrile, acetone], in the presenceof a halide [e.g., alkyl halides (e.g., propyl iodide, isobutyl iodide,ethyl bromoacetate), aralkyl halides (e.g., benzyl chloride)], bystirring the mixture at 0 to 40° C. for 2 to 18 hours. For example, whenethyl bromoacetate is used, the acetic acid ester obtained is reacted atabout 15 to 25° C. for 2 to 12 hours, using an appropriate solvent and abase (e.g., 1 N NaOH in ethyl alcohol). The acetic acid compound isdissolved in an appropriate solvent [e.g., tetrahydrofuran (THF)], andthen, isobutyl chloroformate is added in the presence of an appropriatebase (e.g., triethylamine) and a reaction is carried out at 0° C. for 1to 4 hours. To the reaction solution, an appropriate amine compound(e.g., methylamine, propylamine, piperidine) is added, and a reaction iscarried out at about 0 to 25° C. for 1 to 12 hours.

[0219] The above-described starting compound having the hydroxy group inthe molecule can be produced by, for example, subjecting a compoundhaving the alkoxy group in the molecule to acid hydrolysis. This acidhydrolysis is achieved by a commonly used method; for example, thestarting compound is reacted in an appropriate solvent such as alcohols(e.g., methanol, ethanol) in the presence of 1 N hydrochloric acid atabout 0 to 25° C. for 1 to 10 hours.

[0220] (xi) A compound having an alkanoyl-phenyl group can be producedby introducing an alkanoyl-phenyl group to a compound having ahalogenated group. For introduction of an alkanoyl-phenyl group, ahalogenated compound is first reacted in an appropriate solvent (e.g.,carbon tetrachloride, chloroform) in the presence of N-bromosuccinimideand a catalytic amount (not more than 10 mol %) of2,2′-azobis(isobutyronitrile) at 100 to 120° C. for 1 to 4 hours.

[0221] Introduction of an alkanoyl-phenyl group to the halogenatedcompound is carried out in an appropriate solvent such asdimethoxyethane (DME). To the solution, an alkanoyl-phenyl borate;I apalladium compound [e.g., Pd(PPh₃)₄, Ph represents phenyl] and sodiumcarbonate (2 M, Na₂CO₃) are added. The reaction is carried out in aninert gas stream at about 15 to 120° C. for about 1 to 12 hours.

[0222] An alkanoyl-phenyl borate is produced by reacting analkanoyl-phenyl bromide and a boric acid compound [e.g., (i-PrO)₃B, Prrepresents propyl] in the presence of an appropriate base (e.g., BuLi,Bu represents butyl).

[0223] (xii) A compound having an alkyl-phenyl group can be produced bythe same method as method (xi) above, except that an alkyl-phenyl borateis used in place of an alkanoyl-phenyl borate in the reaction.

[0224] (xiii) In the compound of the present invention, an incorporationof a sulfonamide group can be produced by halogenating the alkyl groupin the starting compound, then subjecting the compound to a nucleophilicsubstitution reaction with a sulfonamide.

[0225] The halogenation is achieved by reacting the starting compound inan appropriate solvent (e.g., carbon tetrachloride) in the presence ofN-bromosuccinimide or a catalytic amount of2,2′-azobis(isobutyronitrile) at 100 to 120° C. for 1 to 4 hours. Thenucleophilic substitution reaction is carried out, for example, in anappropriate solvent such as N,N-dimethylformamide (DMF) in the presenceof n-hexane-washed sodium hydride and a sulfonamide derivative (e.g.,methanesulfonamide, ethanesulfonamide, benzenesulfonamide) at 0 to 40°C. for 1 to 24 hours.

[0226] Introduction of other groups to the compound of the presentinvention can be achieved, using per se known methods.

[0227] Compound (I) of the present invention thus obtained may form asalt. The salt is preferably a physiologically acceptable acid additionsalt. Such salts include, for example, salts with inorganic acids (e.g.,hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid) and physiologically acceptable acid addition salts withorganic acids (e.g., formic acid, acetic acid, trifluoroacetic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid). When compound (I) of the present invention hasan acidic group such as —COOH, it may form a physiologically acceptablesalt with an inorganic base (e.g., alkali metals such as sodium,potassium, calcium and magnesium, alkaline earth metals, ammonia) or anorganic base (e.g., trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine).

[0228] Also, the compound of the present invention or a salt thereof maybe a hydrate or a non-hydrate. The hydrate is exemplified bymonohydrate, sesquihydrate and dehydrate.

[0229] Compound (I) of the present invention or a salt thereof thusobtained may be isolated and purified by ordinary means of separationsuch as recrystallization, distillation and chromatography, etc. Whenthe compound of the present invention is obtained in free form, it canbe converted to a salt by per se known methods or analogous thereto.When the compound of the present invention is obtained in salt form, itcan be converted to the free form or another salt by per se knownmethods or analogous thereto.

[0230] Compound (I) of the present invention or a salt thereof may hasasymmetric carbon. When it is obtained as a mixture (racemate) ofoptically active configurations, it can be fractionated into therespective optically active configurations by ordinary means of opticalresolution.

[0231] Compound (I) or its salt of the present invention (hereinafteralso referred to as “compound of the present invention”) possessesexcellent GnRH-antagonizing activity and low toxicity. In addition, itis excellent in oral absorbability, action sustainability, stability andpharmacokinetics. Furthermore, it can be easily produced. The compoundof the present invention can therefore be safely used in a mammal (e.g.,human, monkey, bovine, horse, dog, cat, rabbit, rat, mouse) forpreventing and/or treating diseases depending on male or femalehormones, diseases due to excess of these hormone, etc., by suppressinggonadotropin secretion by its GnRH receptor-antagonizing action tocontrol blood sex hormone concentrations.

[0232] For example, the compound of the present invention is useful forpreventing and/or treating sex hormone-dependent cancers (e.g.,prostatic cancer, uterine cancer, breast cancer, pituitary tumor),prostatic hypertrophy, hysteromyoma, endometriosis, precocious puberty,amenorrhea, premenstrual syndrome, multilocular ovary syndrome, pimplesetc. The compound of the present invention is also useful for theregulation of reproduction in males or females (e.g., pregnancyregulators, menstruation cycle regulators). The compound of the presentinvention also be used as a male or female contraceptive, or as a femaleovulation inducer. Based on its rebound effect after withdrawal, thecompound of the present invention can be used to treat infertility.

[0233] In addition, the compound of the present invention is useful forregulation of animal estrous, improvement of meat quality and promotionof animal growth in the field of animal husbandry. The compound of thepresent invention is also useful as a fish spawning promoter.

[0234] Although the compound of the present invention can be used alone,it is effective to use it in combination with a steroidal ornon-steroidal anti-androgen agent or anti-estrogen agent. The compoundof the present invention can also be used to suppress the transient risein blood testosterone concentration (flare phenomenon) observed inadministration of a super-agonist such as leuprorelin acetate. Thecompound of the present invention may be used with a chemotherapeuticagent for cancer. A preferred example of such combination is thecompound of the present invention in combination with chemotherapeuticagents such as ifosfamide, UTF, adriamycin, peplomycin and cisplatin forprostatic cancer. For breast cancer, the compound of the presentinvention can be used with chemotherapeutic agents such ascyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C andmitocantrone.

[0235] When the compound of the present invention is used as aprophylactic and/or therapeutic agent for the above-mentioned diseasesor used in the filed of animal husbandry or fishery, it can beadministered orally or non-orally, as formulated with a pharmaceuticallyacceptable carrier, normally in the form of solid preparations such astablets, capsules, granules and powders for oral administration, or inthe form of intravenous, subcutaneous, intramuscular or otherinjections, suppositories or sublingual tablets for non-oraladministration. It may also be sublingually, subcutaneously,intramuscularly or otherwise administered in the form ofsustained-release preparations of sublingual tablets, microcapsules etc.Depending on symptom severity, subject age, sex and weight, duration andintervals of administration, kind of active ingredient etc., daily doseis not subject to limitation. For use in the treatment of theabove-described sex hormone-dependent cancers (e.g., prostatic cancer,uterine cancer, breast cancer, pituitary tumor), prostatic hypertrophy,hysteromyoma, endometriosis, precocious puberty etc., daily dose isnormally about 0.1 to 30 mg, preferably about 0.1 to 10 mg, and morepreferably 0.1 to 5 mg, per kg weight of mammal, normally in 1 to 4divided dosages.

[0236] The above doses are applicable to the use of the compound of thepresent invention in the filed of animal husbandry or fishery. Dailydose is about 0.01 to 10 mg, preferably about 0.05 to 5 mg, per kgweight of subject organism, normally in 1 to 3 divided dosages.

[0237] Pharmaceutically acceptable carriers are various organic orinorganic carrier substances in common use as pharmaceutical materials,including excipients, lubricants, binders and disintegrants for solidpreparations, and solvents, dissolution aids, suspending agents,isotonizing agents, buffers and soothing agents for liquid preparations.Other pharmaceutical additives such as preservatives, antioxidants,coloring agents and sweetening agents may be used as necessary.

[0238] Preferable excipients include, for example, lactose, sucrose,D-mannitol, starch, crystalline cellulose and light silicic anhydride.Preferable lubricants include, for example, magnesium stearate, calciumstearate, talc and colloidal silica. Preferable binders include, forexample, crystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropyl cellulose, hydroxypropylmethyl cellulose andpolyvinylpyrrolidone. Preferable disintegrants include, for example,starch, carboxymethyl cellulose, carboxymethyl cellulose calcium,crosslinked carmellose sodium and carboxymethyl starch sodium.Preferable solvents include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil and corn oil. Preferabledissolution aids include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate and sodium citrate.Preferable suspending agents include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride andmonostearic glycerol; and hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose andhydroxypropyl cellulose. Preferable isotonizing agents include, forexample, sodium chloride, glycerol and D-mannitol. Preferable buffersinclude, for example, buffer solutions of phosphates, acetates,carbonates, citrates etc. Preferable soothing agents include, forexample, benzyl alcohol. Preferable preservatives include, for example,paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid and sorbic acid. Preferable antioxidantsinclude, for example, sulfites and ascorbic acid.

[0239] By adding a suspending agent, a dissolution aid, a stabilizer, anisotonizing agent, a preservative etc., the compound of the presentinvention can be prepared as an intravenous, subcutaneous orintramuscular injection by a commonly known method. In such cases, thecompound of the present invention can be freeze-dried as necessary by acommonly known method. In administration to humans, for example, thecompound of the present invention can be safely administered orally ornon-orally as such or as a pharmaceutical composition prepared by mixingit with a pharmacologically acceptable carrier, excipient and diluentselected as appropriate.

[0240] Such pharmaceutical compositions include oral preparations (e.g.,powders, granules, capsules, tablets), injections, drip infusions,external preparations (e.g., nasal preparations, transdermalpreparations) and suppositories (e.g., rectal suppositories, vaginalsuppositories).

[0241] These preparations can be produced by commonly known methods incommon use for pharmaceutical making processes.

[0242] An injection can be produced by, for example, preparing thecompound of the present invention as an aqueous injection along with adispersing agent (e.g., Tween 80, produced by Atlas Powder Company, USA,HCO 60, produced by Nikko Chemicals Co., Ltd., polyethylene glycol,carboxymethyl cellulose, sodium alginate), a preservative (e.g., methylparaben, propyl paraben, benzyl alcohol), an isotonizing agent (e.g.,sodium chloride, mannitol, sorbitol, glucose) and other additives, or asan oily injection in solution, suspension or emulsion in a vegetable oilsuch as olive oil, sesame oil, cottonseed oil or corn oil, propyleneglycol or the like.

[0243] An oral preparation can be produced by shaping the compound ofthe present invention by a commonly known method after addition of anexcipient (e.g., lactose, sucrose, starch), a disintegrant (e.g.,starch, calcium carbonate), a binder (e.g., starch, gum arabic,carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose),a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000)and other additives, and, where necessary, coating the shaped productfor the purpose of taste masking, enteric dissolution or sustainedrelease by a commonly known method. Coating agents for this purposeinclude, for example, hydroxypropylmethyl cellulose, ethyl cellulose,hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethyleneglycol, Tween 80, Prulonic F68, cellulose acetate phthalate,hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, Eudragit (produced by Rohm Company, Germany, methacrylicacid/acrylic acid copolymer) and dyes (e.g., iron oxide, titaniumdioxide). For an enteric preparation, an intermediate phase may beprovided between the enteric phase and the drug-containing phase for thepurpose of separation of the two phases by a commonly known method.

[0244] An external preparation can be produced by compounding thecompound of the present invention as a solid, semi-solid or liquidcomposition by a commonly known method. Such a solid composition isproduced by, for example, powdering the compound of the presentinvention as such or in mixture with an excipient (e.g., glycol,mannitol, starch, microcrystalline cellulose), a thickening agent (e.g.,natural rubber, cellulose derivative, acrylic acid polymer) and otheradditives. Such a liquid composition is produced by preparing thecompound of the present invention as an oily or aqueous suspension inalmost the same manner as with the injection. The semi-solid compositionis preferably an aqueous or oily gel, or an ointment. All thesecompositions may contain pH regulators (e.g., carbonic acid, phosphoricacid, citric acid, hydrochloric acid, sodium hydroxide), preservatives(e.g., paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride)and other additives.

[0245] A suppository is produced by preparing the compound of thepresent invention as an oily or aqueous solid, semi-solid or liquidcomposition by a commonly known method. Useful oily bases for suchcompositions include glycerides of higher fatty acids (e.g., cacao fat,uitepsols, produced by Dynamite Nobel Company, Germany), moderate fattyacids (e.g., MIGLYOL, produced by Dynamite Nobel Company, Germany), andvegetable oils (e.g., sesame oil, soybean oil, cottonseed oil). Aqueousbases include, for example, polyethylene glycols and propylene glycol.Bases for aqueous gels include, for example, natural rubbers, cellulosederivatives, vinyl polymers and acrylic acid polymers.

BEST MODE FOR CARRYING OUT THE INVENTION

[0246] The present invention is hereinafter described in more detail bymeans of, but is not limited to, the following reference examples,examples, experimental example and preparation examples.

[0247]¹H-NMR spectra are determined with tetramethylsilane as theinternal standard, using the LAMBDA 300 (300 MHz) spectrometer (producedby JEOL, Ltd.) or the Bruker AM500 (500 MHz) spectrometer (produced byBruker); all δ values are shown in ppm.

[0248] The symbols used herein have the following definitions:

[0249] s: singlet

[0250] d: doublet

[0251] t: triplet

[0252] dt: double triplet

[0253] m: multiplet

[0254] q: quartet

[0255] br: broad

[0256] Me: methyl

[0257] Et: ethyl

[0258] Ph: phenyl

[0259] Bz: benzyl

[0260] Boc: t-Butoxycarbonyl

[0261] THF: tetrahydrofuran

[0262] DMF: dimethylformamide

[0263] The term “at room temperature” indicates the range from about 15to 25° C., but is not to be construed as strictly limitative.

Reference Example 1 Production of2-amino-4-hydroxypyrimidine-5-carboxylic acid ethyl ester

[0264]

[0265] Guanidine carbonate (18.0 g, 200 mmol) is dissolved in ethanol(300 ml), and then sodium alcoholate (13.6 g) and ethoxymethylenemalonicacid diethyl ester (43.2 g, 200 mmol) are added at room temperature.After stirring at room temperature for 4 days, the mixture isconcentrated to dryness under reduced pressure. To the residue obtained,water (500 ml) is added and neutralized with hydrochloric acid, and thenthe crystal precipitated is collected by filtration and recrystallized,to yield a white crystal (30.5 g, 83%).

[0266] mp 280° C. (lit. 285° C.: Journal of the Indian Chemical Society,1925, Vol. 2, pp. 61-70)

[0267]¹H-NMR (CDCl₃) δ: 1.25 (3H, t), 4.14 (2H, q), 6.0-7.5 (2H, br s),8.35 (1H, s), 11.12 (1H, br s).

Reference Example 2

[0268] In the same manner as Reference Example 1, with guanidinecarbonate as the starting material, and using 2-benzylacetoacetic acidethyl ester, acetoacetic acid ethyl ester, 2-ethoxymethylenephenylaceticacid ethyl ester, 2-methoxy-2-formylacetic acid ethyl ester,2-butoxy-2-formylacetic acid ethyl ester, or 2-benzyloxy-2-formylaceticacid ethyl ester, in place of ethoxymethylenemalonic acid diethyl ester,the 5,6-substitutional 2-amino-4-hydroxypyrimidine derivatives shown inTable 1 are synthesized. TABLE 1

Compd. yield mp No. R⁵ R⁶ (%) (° C.) 1 Bz Me 72 >250(dc.) 2 H Me84 >250(dc.) 3 Ph H 29 >250(dc.) 4 methoxy H 65 266-267 5 butoxy H 62236-239 6 benzyloxy H 65 245-246

Reference Example 3 Prodution of5,8-dihydro-3-methyl-5-oxo-8-(1-oxo-1-2-propyl)-2-phenylimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0269]

[0270] The pyrimidine compound obtained in Reference Example 1 (10.0 g,54.6 nmol) is dissolved in dimethylformamide (300 ml), and thenpotassium carbonate (18.9 g, 136.5 nmol), potassium iodide (9.10 g, 54.6mmol) and 2-bromopropiophenone (29.1 g, 136.5 mmol) are added. Afterstirring at room temperature for 4 days, the mixture is concentrated todryness under reduced pressure. The residue obtained is dispensed towater (300 ml) and chloroform (300 ml). After extraction withchloroform, the water layer is combined with the organic layer, followedby drying with magnesium sulfate and subsequent concentration underreduced pressure. The residue obtained is purified with silica gel toyield a white crystal (11.3 g), which is then recrystallized from ethylacetate ester and hexane to yield a white needle crystal (8.6 g, 37%).

[0271] mp 177-178° C.

[0272]¹H-NMR (CDCl₃) δ: 1.42 (3H, t), 1.82 (3H, d), 2.90 (3H, s), 4.41(2H, q), 6.82 (1H, q), 7.3-7.4 (3H, m), 7.5-7.7 (5H, m), 8.13 (2H, d),8.54 (1H, s).

Reference Example 4

[0273] Using the compounds obtained in Reference Example 2, and in thesame manner as Reference Example 3, with2-bromo-1-(4-acetylamino)phenylpropan-1-one,2-bromo-1-(4-methoxy)phenylpropan-1-one and2-bromo-1-(4-acetoxy)phenylpropan-1-one in place of2-bromopropiophenone, the derivatives shown in Table 2 are synthesized.TABLE 2

Compd. yield mp No. R¹, R^(1a) R⁵ (%) (° C.) 1 4-acetylamino Ph 25amorphous 2 4-methoxy ethoxy- 30 166-167 carbonyl (free) 3 4-acetoxybromo 30 amorphous

Reference Example 5 Production of 2-amino-5-bromo-4-hydroxypyrimidine

[0274]

[0275] To a solution of isocytosine(1.04 g, 9.36 mmol) in acetic acid(25ml) are added dropwise bromine(0.51 ml, 9.83 mmol) at room temperature.After the addition is completed, the reaction mixture is stirred for 1hour at this temperature, successively concentrated under reducedpressure to give the residue, which is washed with ethyl ether, dried toafford white powders(2.49g, 98%).

EXAMPLE 1 Production of5-hydroxy-3-methyl-2-phenylimidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester

[0276]

[0277] To an acetic acid solution (30 ml) of the compound obtained inReference Example 3 (0.43 g, 1.0 mmol), zinc powder (1.05 g, 16 mmol) isadded, followed by stirring under heating at 80° C. for 2 hours. Thereaction mixture is filtered through Celite to remove the zinc, and thenthe resulting filtrate is concentrated under reduced pressure. The brownsubstance obtained is crystallized by the addition of water (100 ml).After filtration, the crystal is purified by recrystallization(chloroform-hexane-ether) to yield a brownish white needle crystal (0.26g, 87%).

[0278] mp 220-225° C.

[0279]¹H-NMR (CDCl₃) δ: 1.41 (3H, t), 2.93 (3H, s), 4.36 (2H, q), 7.56(5H, s), 8.53 (1H, s).

[0280] IR (KBr): 4426, 3448, 2984, 2368, 1721, 1543, 1456, 1373, 1344,1292, 1209, 1131, 1091, 1023, 922, 853, 795, 768, 700, 669 cm⁻¹.

[0281] FAB-MS Calcd for C₁₆H₁₆N₃O₃ 298.11928, found 298.0681

[0282] Anal. Calcd for C₁₆H₁₅N₃O₃.0.8H₂O: C, 61.65; H, 5.37; N, 13.48.Found: C, 61.83; H, 4.99; N, 13.45.

EXAMPLE 2

[0283] In the same manner as Reference Example 3 (the method describedin Example 2 also conducted as necessary), using the pyrimidinecompounds shown in Reference Example 2 and 2-bromopropiophenone orvarious halogenoketone compounds, the imidazo[1,2-a]pyrimidinederivatives shown in Table 3 are synthesized. TABLE 3

Compd. yd. mp No. R¹, R², R³ R⁴ R⁵ R⁶ (%) (° C.) 1 H Me Bz Me 2 4-cyclo-Me Bz Me 30 amorphous propylmethoxy 3 4-methoxy Me Bz Me 4 4-acetoxy MeBz Me 5 H H Bz Me 6 H H ethoxycarbonyl H 7 4-cyclo- H Bz Mepropylmethoxy 8 4-cyclo- H H Me propylmethoxy 9 4-cyclo- Me Ph Hpropylmethoxy 10 H Me Ph H 11 4-acetoxy Me Ph H 12 H Me methoxy H 134-acetoxy Me methoxy H 14 H Me butoxy H 15 4-acetoxy Me butoxy H 16 H Mebenzyloxy H 17 4-acetoxy Me benzyloxy H 18 4-cyclo- Me ethoxycarbonyl Hpropylmethoxy 19 4-isobutyryl- Me Bz Me 30 amorphous amino 20 4-acetoxyMe ethoxycarbonyl H 26 258-260 21 4-acetylamino Me Ph H 80 amorphous 224-acetylamino Me Bz Me 20 amorphous 23 4-acetoxy Me bromo H 63 >260(dc.)24 4-methoxy Me ethoxycarbonyl H 43 245-247

EXAMPLE 3 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-3-methyl-5-oxo-2-phenylimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0284]

[0285] To a solution of the compound obtained in Example 1 (157 mg, 0.53mmol) in DMF (15 ml), potassium carbonate (80 mg, 0.58 mmol),2,6-difluorobenzyl chloride (103 mg, 0.64 mmol) and potassium iodide (44mg, 0.26 mmol) are added, followed by stirring at about 15 to 25° C. for1 hour and stirring under heating at 80° C. for 1 hour. The brownishwhite crystalline substance obtained by concentration under reducedpressure of the reaction mixture is dispensed to ethyl acetate (30 ml)and water (30 ml). The water layer is extracted with ethyl acetate (10ml), and the organic layers are combined and dried over sodium sulfate,after which the solvent is distilled off under reduced pressure to yielda crude brownish white crystalline product (204 mg), which is thenpurified by flush column chromatography to yield a white crystal (146mg, 65%).

[0286]¹H-NMR (CDCl₃) δ: 1.39 (3H, t), 2.91 (3H, s), 4.37 (2H, g), 5.51(2H, s), 7.00 (2H, t), 7.3-7.5 (4H, m), 7.69 (2H, d), 8.37 (1H, s).

EXAMPLE 4

[0287] Using the compounds obtained in Example 2, and in the same manneras Example 3, the compounds shown in Table 4 below are produced. TABLE 4

Compd. yd. mp No. R¹, R², R³ R⁴ R⁵ R⁶ (%) (° C.) 1 H Me Bz Me 2 4-cyclo-Me Bz Me 20 178-180 propylmethoxy 3 4-methoxy Me Bz Me 4 4-acetoxy Me BzMe 5 H H Bz Me 6 H H ethoxycarbonyl H 7 4-cyclo- H Bz Me propylmethoxy 84-cyclo- H H Me propylmethoxy 9 4-cyclo- Me Ph H propylmethoxy 10 H MePh H 11 4-acetoxy Me Ph H 12 H Me methoxy H 13 4-acetoxy Me methoxy H 14H Me butoxy H 15 4-acetoxy Me butoxy H 16 H Me benzyloxy H 17 4-acetoxyMe benzyloxy H 18 4-cyclo- Me ethoxycarbonyl H propylmethoxy 194-isobutyryl- Me Bz Me 10 179-180 amino 20 4-acetoxy Me ethoxycarbonyl H67 181-182 21 4-acetylamino Me Ph H 73 amorphous 22 4-acetylamino Me BzMe 20 amorphous 23 4-acetoxy Me bromo H 53 203-207 24 4-methoxy Meethoxycarbonyl H 74 195-197

EXAMPLE 5 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-3-methyl-2-(4-nitrophenyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0288]

[0289] To a solution of the compound obtained in Example 3 (3.0 g, 7.0mmol) in concentrated sulfuric acid (30 ml), a solution of sodiumnitrate (0.6 g, 7.0 mmol) in concentrated sulfuric acid (6 ml) is addeddrop by drop under ice cooling conditions over a 30-minute period,followed by stirring under ice cooling conditions for 4 hours. Thereaction mixture is dispensed to water (500 ml) and chloroform (400 ml),and then the water layer is extracted with chloroform (200 ml), and theorganic layers are combined and dried over sodium sulfate, after whichthe solvent is distilled off under reduced pressure to yield a crudeyellow crystalline product, which is then purified by recrystallization(chloroform-ether) to yield a brown-yellow crystal (6, 2.6 g, 80%).

[0290] mp 219-221° C.

[0291]¹H-NMR (CDCl₃) δ: 1.40 (3H, t), 2.97 (3H, s), 4.38 (2H, q), 5.51(2H, s), 7.02 (2H, t), 7.36-7.46 (1H, m), 7.87-8.31 (4H, q), 8.46 (1H,s).

[0292] IR (KBr): 3448, 3086, 2986, 2364, 1746, 1713, 1628, 1599, 1518,1473, 1342, 1290, 1218, 1160, 1108, 1035, 907, 857, 789, 760, 710, 611,580, 499 cm⁻¹.

[0293] FAB-MS m/e 469.1 (MH⁺)

[0294] Anal. Calcd for C₂₃H₁₈N₄O₅F₂: C, 58.98; H, 3.87; N, 11.96. Found:C, 58.49; H, 3.79; N, 12.01.

EXAMPLE 6

[0295] Using the compounds obtained in Example 4, and in the same manneras Example 5, the compounds shown in Table 5 below are produced. TABLE 5

Compd. No. R⁴ R⁵ R⁶ 1 Me Bz Me 2 H Bz Me 3 H ethoxycarbonyl H 4 Me Ph H5 Me methoxy H 6 Me butoxy H 7 Me benzyloxy H

EXAMPLE 7 Production of3-bromomethyl-8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-nitrophenyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0296]

[0297] A suspension of the compound obtained in Example 5 (0.79 g, 1.7mmol), N-bromosuccinimide (0.33 g, 1.86 mmol) and2,2′-azobis(isobutyronitrile) (55 mg, 0.34 mmol) in carbon tetrachloride(150 ml) is refluxed under heating for 4 hours to yield a transparentbrown solution. The reaction mixture is concentrated under reducedpressure to distill off half the solvent, after which it is dispensed tochloroform (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (200 ml). The water layer is extracted with chloroform (100ml), and then the organic layers are combined and dried over sodiumsulfate, after which the solvent is distilled off under reduced pressureto yield a crude brown crystalline product (1.07 g), which is thenpurified by recrystallization (methylene chloride-ether) to yield abrown crystal (0.74 g, 80%).

[0298] mp 205-210° C.

[0299]¹-NMR (CDCl₃) δ: 1.40 (3H, t), 4.49 (2H, q), 5.31 (2H, s), 5.54(2H, s), 7.02 (2H, t), 7.37-7.47 (1H, m), 8.04-8.38 (4H, q), 8.53 (1H,s).

[0300] IR (KBr): 4386, 3436, 3080, 2986, 1748, 1717, 1630, 1580, 1530,1473, 1344, 1296, 1224, 1160, 1091, 1035, 855, 791, 719, 698, 613, 586,499, 429 cm⁻¹.

[0301] Anal. Calcd for C₂₃H₁₇N₄O₅F₂Br: C, 50.47; H, 3.13; N, 10.24.Found: C, 50.58; H, 3.25; N, 10.23.

EXAMPLE 8

[0302] Using the compounds obtained in Examples 4 and 6, and in the samemanner as Example 7, the compounds shown in Table 6 below are produced.TABLE 6

Compd. yd. mp No. R¹, R², R³ R⁵ R⁶ (%) (° C.) 1 4-nitro Bz Me 2 4-nitroPh H 3 4-nitro methoxy H 4 4-nitro butoxy H 5 4-nitro benzyloxy H 64-cyclo- Bz Me 80 amorphous propylmethoxy 7 4-methoxy Bz Me 8 4-acetoxyBz Me 9 4-cyclo- Ph H propylmethoxy 10 4-acetoxy Ph H 11 4-acetoxymethoxy H 12 4-acetoxy butoxy H 13 4-acetoxy benzyloxy H 14 4-(N-Boc-N-Ph H 60 amorphous acetylamino) 15 4-(N-Boc-N- Bz Me 80 amorphousacetylamino) 16 4-cyclo- Ph H 80 amorphous propylmethoxy 17 4-cyclo-4-chlorophenyl H 90 amorphous propylmethoxy 18 4-cyclo- 4-methoxyphenylH 75 amorphous propylmethoxy 19 4-nitro 4-(3-methylbutyryl) H 72amorphous 20 4-methoxy ethoxycarbonyl H 80 amorphous 21 4-acetoxyethoxycarbonyl H 90 amorphous

EXAMPLE 9 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-3-(N-methyl-N-benzylaminomethyl)-2-(4-nitrophenyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0303]

[0304] To a solution of the compound obtained in Example 7 (1.3 g, 10mmol) in DMF (50 ml), N-ethyldiisopropylamine (1.3 g, 10 mmol) andN-methylbenzylamine (0.7 g, 6 mmol) are added, followed by overnightstirring at about 15 to 25° C. The brown substance obtained byconcentration under reduced pressure of the reaction mixture isdispensed to a saturated aqueous solution of sodium hydrogen carbonate(300 ml) and ethyl acetate (200 ml). The water layer is extracted withethyl acetate (50 ml), and then the organic layers are combined, washedwith saturated saline (300 ml), and dried over sodium sulfate, afterwhich the solvent is distilled off under reduced pressure to yield acrude brown crystalline product (2.2 g), which is then purified by flushcolumn chromatography and recrystallized from dichloromethane-n-hexaneto yield a yellow crystal (1.42 g, 56%).

[0305] mp 187-189° C.

[0306]¹H-NMR (CDCl₃) δ: 1.40 (3H, t), 2.27 (3H, s), 3.69 (2H, s), 4.37(2H, s), 4.40 (2H, q), 5.51 (2H, s), 6.99 (2H, t), 7.16-7.46 (6H, m),8.26-8.33 (4H, q), 8.48 (1H, s).

[0307] IR (KBr): 4470, 3452, 2982, 2364, 1746, 1715, 1630, 1603, 1516,1475, 1344, 1301, 1214, 1174, 1100, 1036, 855, 789, 748, 700, 499 cm⁻¹.

[0308] FAB-MS m/e 588.4 (MH⁺)

[0309] Anal. Calcd for C₃₁H₂₇N₅O₅F₂.0.7H₂O: C, 62.04; H, 4.77; N, 11.67.Found: C, 62.03; H, 4.47; N, 11.35.

EXAMPLE 10

[0310] Using the compounds obtained in Example 8, and in the same manneras Example 9, the compounds shown in Table 7 below are produced. TABLE 7

Cpd. yd. mp No. R¹, R², R³ R⁴ R⁵ R⁶ (%) (° C.) 1 4-nitro *) Bz Me 24-nitro *) Ph H 3 4-nitro *) methoxy H 4 4-nitro *) butoxy H 5 4-nitro*) benzyloxy H 6 4-cyclo- *) Bz Me 71 hydrochloride propylmethoxy172-176 7 4-methoxy *) benzyl Me 8 4-acetoxy *) Bz Me 9 4-cyclo- *) Ph Hpropylmethoxy 10 4-acetoxy *) Ph H 11 4-acetoxy *) methoxy H 124-acetoxy *) butoxy H 13 4-acetoxy *) benzyloxy H 14 4-isobutyryl- *) BzMe 4 hydrochloride amino 165-168 15 4-nitro **) ethoxycarbonyl H 59amorphous 16 4-(N-Boc-N- *) phenyl H 80 amorphous acetylamino) 174-(N-Boc-N- *) Bz Me 80 amorphous acetylamino) 18 4-cyclo- *) Ph H 75amorphous propylmethoxy 19 4-cyclo- *) 4-chlorophenyl H 70 amorphouspropylmethoxy 155-161 (hydrochloride) 20 4-cyclo- *) 4- H 73 amorphouspropylmethoxy methoxyphenyl 184-187 (hydrochloride) 21 4-nitro *) 4-(3-H 83 amorphous methylbutyryl) 22 4-methoxy *) ethoxycarbonyl H 43190-192 hydrochloride 23 4-acetoxy *) ethoxycarbonyl H 85 amorphous

EXAMPLE 11 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-3-(hydroxymethyl)-2-(4-nitrophenyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0311]

[0312] The by-product in Example 7 (obtained before recrystallizingprocedure with methylene chloride-n-hexane) is purified byrecrystallization (methylene chloride-n-hexane) to yield a brown-yellowcrystal (0.14 g).

[0313] mp 230-232° C.

[0314]¹H-NMR (CDCl₃) δ: 1.40 (3H, t), 3.68 (1H, t), 4.41 (2H, q), 5.01(2H, d), 5.56 (2H, s), 7.03 (2H, t), 7.38-7.48 (1H, m), 7.88-8.33 (4H,q), 8.55 (1H, s).

[0315] IR (KBr): 3460, 1736, 1601, 1518, 1475, 1344, 1299, 1216, 1106,1038, 855, 7931 719, 499cm⁻¹.

[0316] FAB-MS m/e 485.0 (MH⁺)

[0317] Anal. Calcd for C₂₃H₁₈N₄O₆F₂.0.3H₂O: C, 56.04; H, 3.83; N, 11.44.Found: C, 56.46; H, 3.64; N, 11.37.

EXAMPLE 12 Production of2-(4-aminophenyl)-8-(2,6-difluorobenzyl)-5,8-dihydro-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0318]

[0319] To a solution of the compound obtained in Example 9 (1.0 g, 1.7mmol) and iron powder (0.5 g, 8.5 mmol) in ethanol (20 ml), concentratedhydrochloric acid (10 ml) is added drop by drop under ice coolingconditions over a 1-hour period, followed by stirring under ice coolingconditions for 4 hours, to yield a blackish green suspension. To thereaction mixture, a saturated aqueous solution of sodium hydrogencarbonate (100 ml), chloroform (200 ml) and Celite are carefully addedunder ice cooling conditions, followed by stirring, to yield a graysuspension, which is then filtered, after which the organic layer isdispensed. The water layer is extracted with chloroform (100 ml), andthen the organic layers are combined, washed with a saturated solutionof sodium hydrogen carbonate (200 ml), and dried over sodium sulfate,after which the solvent is distilled off under reduced pressure to yielda crude dark brown product (1.1 g), which is then purified by flushcolumn chromatography to yield a red-brown substance (1.04 g), which isthen recrystallized (methylene chloride-n-hexane) to yield a red-browncrystal (0.86 g, 91%).

[0320] mp 161-166° C.

[0321]¹-NMR (CDCl₃) δ: 1.38 (3H, t), 2.17 (3H, S), 3.65 (2H, s), 3.78(2H, bs, NH₂), 4.31 (2H, s), 4.38 (2H, q), 5.50 S), 6.74-7.88 (4H, q),6.96-7.43 (8H, m), 8.37 (1H, s).

[0322] IR (KBr): 4566, 3366, 2980, 2362, 1740, 1705, 1591, 1510, 1473,1392, 1371, 1301, 1214, 1183, 1102, 1036, 903, 839, 791, 737, 702, 607,499 cm⁻¹.

[0323] MS m/e 558.2 (MH⁺)

[0324] Anal. Calcd for C₃₁H₂₉N₅O₃F₂.0.3H₂O: C, 66.14; H, 5.30; N, 12.44.Found: C, 66.15; H, 5.35; N, 12.44.

EXAMPLE 13

[0325] Using the compounds obtained in Example 10, and in same manner asExample 12, the compounds shown in Table 8 below are produced. TABLE 8

Cpd. yd. mp No. R⁴ R⁵ R⁶ (%) (° C.) 1 N-methyl-N-benzylamino- Bz Memethyl 2 N-methyl-N-benzylamino- Ph H methyl 3 N-methyl-N-benzylamino-methoxy H methyl 4 N-methyl-N-benzylamino- butoxy H methyl 5N-methyl-N-benzylamino- benzyloxy H methyl 6 N′,N′-diethyl-N-methyl-ethoxy- H 97 amorphous ethylenediaminomethyl carbonyl 7N-methyl-N-benzylamino- 4-(3- H 30 amorphous methyl methyl- butyryl)

EXAMPLE 14 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-isobutyrylaminophenyl)-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0326]

[0327] To a solution of the compound obtained in Example 12 (0.28 g, 0.5mmol) and triethylamine (0.2 g, 2.0 mmol) in dichloromethane (25 ml),isobutyryl chloride (0.11 g, 1.0 mmol) is added drop by drop under icecooling conditions over a 1-minute period, followed by stirring underice cooling conditions for 1 hour. The reaction mixture is dispensed todichloromethane (30 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (30 ml). The water layer is extracted withdichloromethane (20 ml), and then the organic layers are combined anddried over sodium sulfate, after which the solvent is distilled offunder reduced pressure to yield a crude red-brown product (0.3 g), whichis then purified by flush column chromatography to yield a red-browncrystalline substance (0.24 g), which is then recrystallized (methylenechloride-n-hexane) to yield a red-brown crystal (0.22 g, 70%).

[0328] mp 98-103° C.

[0329]¹H-NMR (CDCl₃) δ: 1.28 (6H, d), 1.39 (3H, t), 2.18 (3H, s),2.50-2.59 (1H, m), 3.66 (2H, s), 4.34 (2H, s), 4.39 (2H, g), 5.50 (2H,s), 6.99 (2H, t), 7.14-7.44 (6H, m), 7.62-8.04 (4H, q), 8.40 (1H, s).

[0330] IR (KBr): 4386, 3338, 2976, 2364, 1742, 1702, 1601, 1510, 1473,1371, 1303, 1214, 1185, 1100, 1036, 847, 791, 737, 700, 501 cm⁻¹.

[0331] FAB-MS m/e 628.3 (MH⁺)

[0332] Anal. Calcd for C₃₅H₃₅N₅O₄F₂.0.5H₂O: C, 66.03; H, 5.70; N, 11.00.Found: C, 66.08; H, 5.44; N, 11.04.

EXAMPLE 15 Production of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-ethylaminocarbonylaminophenyl)-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0333]

[0334] To a solution of the compound obtained in Example 12 (0.30 g,0.54 mmol) in pyridine (10 ml), ethyl isocyanate (0.20 g, 2.8 mmol) is,followed by overnight stirring at about 15 to 25° C. The brown substanceobtained by concentration under reduced pressure of the reaction mixtureis dispensed to methylene chloride (40 ml) and a saturated aqueoussolution of sodium hydrogen carbonate (40 ml). The water layer isextracted with methylene chloride (20 ml), and then the organic layersare combined and dried over sodium sulfate, after which the solvent isdistilled off under reduced pressure to yield a crude brown product(0.32 g), which is then purified by flush column chromatography to yielda reddish white crystalline substance (0.27 g), which is thenrecrystallized (methylene chloride-n-hexane) to yield a brown crystal(0.22 g, 65%).

[0335] mp 191-196° C.

[0336]¹H-NMR (CDCl₃) δ:1.17 (3H, t), 1.38 (3H, t), 2.17 (3H, s),3.28-3.37 (1H, m), 3.64 (2H, s), 4.31 (2H, s), 4.38 (2H, q), 5.01 (1H,bs), 5.50 (2H, s), 6.69 (1H, s), 6.99 (2H, t), 7.11-8.01 (10H, m), 8.40(1H, s).

[0337] IR (KBr): 4558, 4474, 3372, 2980, 2366, 1734, 1686, 1601, 1543,1510, 1473, 1375, 1305, 1238, 1185, 1102, 1036, 845, 791, 737, 702, 503cm⁻¹.

[0338] FAB-MS m/e 629.3 (MH⁺)

[0339] Anal. Calcd for C₃₄H₃₄N₆O₄F₂.1.15H₂O: C, 62.87; H, 5.63; N,12.94. Found: C, 62.87; H, 5.23; N, 13.28.

EXAMPLE 16

[0340] Using the compounds obtained in Example 13 and isobutyryl, ethylisocyanate, various acid chlorides and isocyanate derivatives, and inthe same manner as Examples 14 and 15, the compounds shown in Table 9below TABLE 9

Cpd. yd. mp No. R¹, R², R³ R⁴ R⁵ R⁶ (%) (° C.) 1 4-ethylamino- *) Bz Mecarbonylamino 2 4-isobutyrylamino *) Bz Me 3 4-ethylamino- *) Ph Hcarbonylamino 4 4-isobutyrylamino *) Ph H 5 4-ethylamino- *) methoxy Hcarbonylamino 6 4-isobutyrylamino *) methoxy H 7 4-ethylamino- *) butoxyH carbonylamino 8 4-isobutyrylamino *) butoxy H 9 4-ethylamino- *)benzyloxy H carbonylamino 10 4-isobutyrylamino *) benzyloxy H 114-isobutyrylamino **) ethoxy- H 21 hydrochloride carbonyl 149-153 124-ethylamino- **) ethoxy- H 54 hydrochloride carbonylamino carbonyl142-146 13 4-(4-pyridyl- *) ethoxy- H aminocarbonyl- carbonyl amino) 144-(3-furyl- *) Ph H 100 hydrochloride carbonylamino) 185-190 154-(3-furyl- *) Bz Me 82 hydrochloride carbonylamino) 193-199 164-(methoxy- *) Bz Me 27  97-99 amino-) (free) carbonylamino) 174-(3-furyl- *) ***) H 51 195-196 carbonylamino) (free) 18 cyclopropane-*) ***) H 9 amorphous carbonylamino 19 4-(3-furyl- *) 4-(3- H 50hydrochloride carbonylamino) methyl- 149-153 butyryl)

EXAMPLE 17 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-(N-Boc-N-acetylamino)phenyl)-3-methyl-6-benzyl-7-methyl-5-oxoimidazo[1,2-a]pyrimidine

[0341]

[0342] To a solution of the compound No. 22 obtained in Example 4 (51.4g) and dimethylaminopyridine (24.5 g, 0.20 nmol) in dichloromethane (300ml) is added (Boc)₂O (52.4 g, 0.24 mmol) with ice-cooling, successivelythe mixture is stirred at room temperature for 30 minuets. It is washedwith dil. hydrochloric acid solution, and saturated saline, dried overNa₂SO₄, and the solvent is removed under reduced pressure to give theresidue, which is chromatographed on silica gel to afford a yellowamorphous (44.4 g, 72%). A part of the amorphous (3.1 g) isrecrystallized from ethyl acetate-n-hexane to give white crystallinepowders (2.84 g, 66%).

[0343] mp 176-177° C.

[0344] FAB-MS m/e 613.2 (MH⁺)

[0345]¹H-NMR (CDCl₃) δ: 1.40(9H, s), 2.19(3H, s), 2.56(3H, s), 2.92(3H,s), 3.97(2H, s), 5.67(2H, s), 6.88(2H, s), 7.11-7.36(8H, m), 8.03(2H.d).

EXAMPLE 18 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-(N-Boc-N-acetylamino)phenyl)-3-methyl-6-phenyl-5-oxoimidazo[1,2-a]pyrimidine

[0346]

[0347] Using the compound No. 21 obtained in Example 4, and in the samemanner as Example 17,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-(N-Boc-N-acetylamino)phenyl)-3-methyl-6-phenyl-5-oxoimidazo[1,2-a]pyrimidineis produced as white crystalline powders (yield, 70%).

[0348] mp 220-222° C.

EXAMPLE 19 Preparation of2-[4-(N-Boc-amino)phenyl]-8-(2,6-difluorobenzyl)-5,8-dihydro-3-(N-methyl-N-benzylaminomethyl)-6-benzyl-7-methyl-5-oxoimidazo[1,2-a]pyrimidine

[0349]

[0350] To a solution of the compound No. 17 obtained in Example 10 (0.65g, 0.89 nmol) in THF (30 ml) is added a solution of sodium methoxide inmethanol (28%, 3.0 ml) with ice-cooling. An additional solution ofsodium methoxide in methanol (28%, 9.0 ml) is added at this temperatureand is stirred for 1 hour at room temperature. The reaction mixture ispartitioned between ethyl acetate (50ml) and saturated saline. Theaqueous layer is extracted with ethyl acetate (50 ml). The combinedorganic solution is washed with saturated saline (20 ml), dried overNa₂SO₄, successively evaporated under reduced pressure to afford acolorless amorphous (0.61 g, 100%). A part of this amorphous (0.08 g) isdissolved in ethyl acetate (3 ml). To this solution is added 1M HClether solution (0.174 ml) with ice-cooling. The residual solid isrecrystallized from ethanol-dichloromethane-ethyl ether to afford whitecrystalline powders (0.057 g, 68%).

[0351] mp 179-184° C.

[0352] FAB-MS m/e 690.2 (MH⁺).

EXAMPLE 20 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-(N-Boc-amino)phenyl)-3-(N-methyl-N-benzylaminomethyl)-6-phenyl-5-oxoimidazo[1,2-a]pyrimidine

[0353]

[0354] Using the compound No. 16 obtained in Example 10, and in the samemanner as Example 19,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-(N-Boc-amino)phenyl)-3-(N-methyl-N-benzylaminomethyl)-6-phenyl-5-oxoimidazo[1,2-a]pyrimidineis produced as a white amorphous (yield, 96%).

EXAMPLE 21 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-aminophenyl)-3-(N-methyl-N-benzylaminomethyl)-6-benzyl-7-methy-5-oxoimidazol1,2-a]pyrimidine

[0355]

[0356] To a solution of the compound obtained in Example 19 (0.53 g,0.77 mmol) in dichloromethane (20 ml) is added trifluoroacetic acid(0.24 ml, 3.07 mmol) with ice-cooling. An additional amount oftrifluoroacetic acid (1.5 ml) is added at room temperature and isstirred for 5 hours at room temperature. The reaction mixture ispartitioned between chloroform (100 ml) and aqueous saturated NaHCO₃solution (30 ml). The aqueous layer is extracted with chloroform (30ml). The combined organic solution is washed with saturated saline (20ml), dried over Na₂SO₄, successively evaporated under reduced pressureto give the residue, which is chromatographed on silica gel to afford apale brown colorless amorphous (0.41 g, 90%).

[0357] FAB-MS m/e 590.1(MH⁺)

EXAMPLE 22 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-aminophenyl)-3-(N-methyl-N-benzylaminomethyl)-6-phenyl-5-oxoimidazo[1,2-a]pyrimidine

[0358]

[0359] Using the compounds obtained in Example 20, and in the samemanner as Example 21,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-aminophenyl)-3-(N-methyl-N-benzylaminomethyl)-6-phenyl-5-oxoimidazo[1,2-a]pyrimidineis produced as a white amorphous (yield, 83%).

EXAMPLE 23 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-hydroxyphenyl)-3-methyl-6-bromo-5-oxoimidazo[1,2-a]pyrimidine

[0360]

[0361] To a solution of the compound No. 23 obtained In Example 4 (0.27g, 0.55 mmnol) in THF (30 ml) is added a solution of K₂CO₃ (0.152 g,1.11 mmol) in water (2 ml). The reaction mixture is stirred at 60° C.for 30 minutes. To the mixture is added 1N aqueous NaOH solution (5 ml).Then the reaction mixture is stirred at 60° C. for 1 hours, successivelyis partitioned between ethyl acetate (100 ml) and dil. hydrochloric acidsolution(30 ml). The aqueous layer is extracted with ethyl acetate (30ml). The combined organic solution is washed with saturated saline (20ml), dried over Na₂SO₄, successively evaporated under reduced pressureto give a pale yellow amorphous (0.25 g, 100%).

[0362]¹H-NMR(CDCl₃) δ: 2.85(3H, s), 5.46(2H, s), 6.68(2H, t),6.87-7.14(3H, m), 7.39(2H, d), 7.56(1H, s), 8.17(1H, s).

EXAMPLE 24 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-bromo-5-oxoimidazo[1,2-a]pyrimidine

[0363]

[0364] To a solution of the compound obtained in Example 23 (0.25 g,0.56 mmol) in DMF (30 ml) is added (bromomethyl)cyclopropane (0.114 g,0.84 mmol), K₂CO₃ (0.116 g, 0.84 mmol) and KI (0.047 g, 0.28 nmol). Theresidual reaction mixture is stirred at 60° C. for 4 hours. To thismixture is added (bromomethyl)cyclopropane (0.14 g, 1.0 mmol). It isstirred at this temperature for 21 hours and is evaporated under reducedpressure to afford the residue, which is partitioned between chloroform(100 ml) and aqueous saturated NaHCO₃ solution (30 ml). The aqueouslayer is extracted with chloroform (30 ml). The combined organic extractis dried over Na₂SO₄ and concentrated under reduced pressure to give theresidue, which is chromatographed on silica gel to afford white crystals(0.23 g, 82%).

[0365] mp 230-231° C.

[0366]¹H-NMR(CDCl₃) δ: 0.38-0.40(2H, m), 0.62-0.68 (2H, m),1.22-1.29(1H, m), 2.85(3H, s), 3.84(2H, d), 5.44(2H, s), 6.91-7.02(4H,m), 7.34-7.44(7H, m), 7.60-7.65(3H, m).

EXAMPLE 25 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-phenyl-5-oxoimidazo[1,2-a]pyrimidine

[0367]

[0368] The compound obtained in Example 24 (0.02 g, 0.04 mmol) is addedto DME (30 ml), which is oxygen free. To this mixture is addedphenylboronic acid (0.0054 g, 0.044 mmol), 2N aqueous K₂CO₃ solution(0.1 ml), tetrakis(triphenylphosphine)palladium(0) (0.0046 g, 0.004mmol). Then the mixture is refluxed for 3 hours under argon atmosphere.The residual reaction mixture is partitioned between ethyl acetate (100ml) and water (30 ml). The aqueous layer is extracted with ethyl acetate(30 ml). The combined organic extract is dried over Na₂SO₄ andconcentrated under reduced pressure to give the residue, which ischromatographed on silica gel to afford white crystals (0.016 g, 78%).

[0369] mp 210-214° C.

[0370]¹H-NMR(CDCl₃) δ: 0.35-0.40(2H, m), 0.63-0.68(2H, m), 1.23-1.31(1H,m), 2.90(3H, s), 3.85(2H, d), 5.50(2H, s), 6.95-7.01(4H, m),7.29-7.50(4H, m), 7.51-7.55(3H, m), 7.67(2H, d).

EXAMPLE 26-1 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-(4-chlorophenyl)-5-oxoimidazo[1,2-a]pyrimidine

[0371]

[0372] Using the compounds obtained in Example 24, and in the samemanner as Example 25, with (4-chlorophenyl)boronic acid in place ofphenylboronic acid,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-(4-chlorophenyl)-5-oxoimidazo(1,2-a]pyrimidineis produced as white crystals (yield, 66%).

[0373] mp 203-205° C.

EXAMPLE 26-2 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-(4-methoxyphenyl)-5-oxoimidazo[1,2-a]pyrimidine

[0374]

[0375] Using the compounds obtained in Example 24, and in the samemanner as Example 25, with (4-methoxyphenyl)boronic acid in place ofphenylboronic acid,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-cyclopropylmethoxyphenyl)-3-methyl-6-(4-methoxyphenyl)-5-oxoimidazo[1,2-a]pyrimidineis produced as white crystals (yield, 66%).

[0376] mp 192-193° C.

EXAMPLE 27 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-phenyl-3-methyl-5-oxoimidazo[1,2-a]pyrimidine-6-(N-methy-N-methoxy)carboxyamide

[0377]

[0378] To a well stirring suspension of N,O-dimethylhydroxyaminehydrochloride (10.5 g) in dichloromethane (210 ml) is added dropwise asolution of dimethylaluminum chloride (1.05 M hexane solution, 100 ml)with ice-cooling. After generating a gas has ceased, to this mixture isadded a solution of the compound obtained in Example 3 (3.81 g, 9 mmol)in dichloromethane (60 ml). The reaction mixture is stirred overnight.To the mixture is added water (30 ml), successively is extracted withchloroform(100 ml×2). The organic extract is dried over Na₂SO₄,evaporated under reduced pressure to give the residue, which ischromatographed on silica gel to afford white crystalline powders (1.99g, 50%).

[0379]¹H-NMR (CDCl₃) δ: 2.90(3H, t), 3.32(3H, s), 3.71(3H, s), 5.48(2H,s), 6.99(2H, t), 7.30-7.50(4H, m), 7.65-7.80(2H, m), 7.74(1H, s).

EXAMPLE 28 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-phenyl-3-methyl-6-(3-methylbutyryl)-5-oxoimidazo[1,2-a]pyrimidine

[0380]

[0381] To a solution of the compound obtained in Example 27 (0.35 g, 0.8mmol) in THF (35 ml) is added isobutylmagnesium bromide (2 M ethyl ethersolution, 4 ml) with ice-cooling. After the addition is completed, themixture is stirred overnight. To this mixture is added 1N hydrochloricacid solution (30 ml). The residual reaction mixture is extracted withchloroform (100 ml×2). The organic extract is dried over Na₂SO₄ andconcentrated under reduced pressure to give the residue, which ischromatographed on silica gel to afford white crystals (0.18 g, 52%).

[0382]¹H-NMR (CDCl₃) δ: 0.98(6H,d), 2.25(1H,m), 2.92(3H,s), 2.99(2h,d),5.53(2H,s), 7.00(2H,t), 7.30-7.50(4H,m), 7.65-7.75(2H,m), 8.37(1H, s).

EXAMPLE 29 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-nitrophenyl)-3-methyl-6-(3-methylbutyryl)-5-oxoimidazo[1,2-a]pyrimidine

[0383]

[0384] To a solution of the compound obtained in Example 28 (0.10 g,0.23 mmol) in conc. sulfuric acid (2 ml) is added dropwise a solution ofsodium nitrite in sulfuric acid (1 M, 0.23 ml) with ice-cooling. In thesame manner as Example 3, the compound,8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-nitrophenyl)-3-methyl-6-(3-methylbutyryl)-5-oxoimidazo[1,2-a]pyrimidineis given as yellow crystals.

EXAMPLE 30 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-aminophenyl)-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-(N-methyl-N-methoxy)carboxamide

[0385]

[0386] To a well stirring suspension of N,O-dimethylhydroxyaminehydrochloride (8.88 g) in dichloromethane (180 ml) is added dropwise asolution of dimethylaluminum chloride (1.05 M hexane solution, 88.8 ml)with ice-cooling. After generating a gas ceases, to this mixture isadded a solution of the compound obtained in Example 12 (4.44 g, 8 mmol)in dichloromethane (80 ml). The reaction mixture is stirred for 1 hourat room temperature. To the mixture is added water (30 ml), successivelyis extracted with ethyl acetate (100 ml×2). The organic extract is diedover Na₂SO₄, evaporated under reduced pressure to give the residue,which is chromatographed on silica gel to afford white crystallinepowders (1.86 g, 41%).

[0387]¹H-NMR (CDCl₃) δ: 2.17(3H, s), 3.33(3H, s), 3.59(2H,s), 3.71(3H,s), 4.31(2H, s), 5.48(2H, s), 6.76(2H, d), 6.99(2H, t), 7.15-7.50(6H,m), 7.75(1H, s), 7.87(2H, d).

EXAMPLE 31 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(3-furylcarbonylaminophenyl)-3-(N-methyl-N-benzylaminomethyl)-6-benzoyl-5-oxoimidazo[1,2-a]pyrimidine

[0388]

[0389] To a solution of the compound No. 17 obtained in Example 16 (0.10g, 0.15 mmol) in THF (6 ml) is added phenylmagnesium bromide (2 M ethylether solution, 0.08 ml) with ice-cooling. After the addition iscompleted, the mixture is stirred overnight. To this mixture is addedcarefully aqueous saturated NaHCO₃ solution (30 ml). The residualreaction mixture is extracted with ethyl acetate (30 ml×2). The organicextract is dried over Na₂SO₄ and concentrated under reduced pressure togive the residue, which is chromatographed on silica gel to afford whitecrystals (0.022 g, 16%).

[0390] mp 194-202° C.

[0391]¹H-NMR (CDCl₃) δ: 2.15(3H, s), 3.60(2, s), 4.31(2H, s), 5.54(2H,s), 6.76(1H, d), 7.01(2H, t), 7.10-7.60(11H, m), 7.70(2H, d), 7.81(2H,d), 8.04(1H, s), 8.07(2H, s).

EXAMPLE 32 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-aminophenyl)-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester

[0392]

[0393] To a solution of the compound obtained in Example 12 (0.10 g,0.18 mmol) in chloroform (5 ml) is added a solution of titanium(IV)isopropoxide (0.3 ml, 1.0 mmol) in 2-propanol (10 ml). Then the mixtureis refluxed at 80° C. for 8 hours, successively is stirred at roomtemperature for 150 minutes. To this mixture is added a mixture ofchloroform (50 ml) and water (50 ml). The aqueous layer is extractedwith chloroform (20 ml). The combined organic extract is dried overNa₂SO₄ and concentrated under reduced pressure to give the residue,which is chromatographed on silica gel to afford white-brown crystallinesolid, which is recrystallized from chloroform-n-hexane to afford palebrown crystals (0.58 g, 94%).

[0394] mp 168-170° C.

[0395]¹H-NMR (CDCl₃) δ: 1.36 (6H, d), 2.15(3H, s), 3.65(3H, s), 3.76(2H,brs), 4.32(2H, s), 5.18-5.26(1H, m), 5.49(2H, s), 6.75(2H, d), 6.99(2H,t), 7.11-7.43(6H, m), 7.85(2H, d), 8.32(1H, s).

EXAMPLE 33 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(methoxyaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester

[0396]

[0397] To a solution of the compound obtained in Example 32 (1.39 g,2.43 mmol) in dichloromethane (30 ml) are added1,1′-carbonyldi-imidazole (0.79 g, 4.86 mmol) and triethylaminie (0.68ml, 4.86 mmol) with ice-cooling. Then the mixture is stirred at roomtemperature for 2 days. To this reaction mixture is addedO-methylhydroxyamine hydrochloride(1.02 g, 12.2 mmol) and triethylamine(1.71 ml, 12.2 mmol) with ice-cooling. The reaction mixture is stirredat this temperature for 4 hours. To the residual mixture is added amixture of chloroform (50 ml) and water (50 ml). The aqueous layer isextracted with chloroform (50 ml). The combined organic extract is driedover Na₂SO₄ and concentrated under reduced pressure to give the yellowresidue, which is chromatographed on silica gel to afford white-browncrystalline solid. The solid is recrystallized from 2-propanol-ethylacetate-isopropyl ether to afford pale yellow crystals (1.15 g, 73%).

[0398] mp 156-158° C.

[0399]¹H-NMR (CDCl₃) δ: 1.36 (6H, d), 2.17 (3H, s), 3.66 (2H, s),3.83(3H, s), 4.33 (2H, s), 5.19-5.27(1H, m), 5.50 (2H, s), 6.99 (2H, t),7.02-7.26(5H, m), 7.34-7.43(1H, m), 7.58(2H, d), 8.03(2H, d), 8.37(1H,s).

[0400] Anal. Calcd for C₃₄H₃₄N₆O₅F₂: C, 63.34; H, 5.32; N, 13.04. Found:C, 63.64; H, 5.26; N, 12.86.

EXAMPLE 34 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester

[0401]

[0402] To a solution of the compound obtained in Example 32 (1.37 g,2.40 mmol) in THF (3 ml) is added pyridine (0.5 ml) and ethyl isocyanate(0.38 ml, 4.8 mmol). Then the mixture is stirred at room temperatureovernight. The reaction mixture is concentrated under reduced pressureto give the residue, which triturated with isopropyl ether to afford acrystalline solid, which is recrystallized from chloroform-isopropylether to afford pale yellow crystals (1.20 g, 78%).

[0403] mp 198-200° C.

[0404]¹H-NMR (CDCl₃) δ: 1.18(3H, t), 1.36(6H, d), 2.16 (3H, s),3.28-3.37(1H, m), 3.64(2H, s), 4.32(2H, s), 4.94(1H, t), 5.19-5.27(1H,m), 5.49(2H, s), 6.58(1H, s), 6.99(2H, t), 7.12-7.26(6H, m), 7.39(2H,d), 7.99(2H, d), 8.36(1H, s).

[0405] Anal. Calcd for C₃₅H₃₆N₆O₄F₂: C, 65.41; H, 5.65; N, 13.08. Found:C, 65.20; H, 5.60; N, 12.87.

EXAMPLE 35

[0406] Using the compounds obtained in Example 12 and various alkylisocyanate derivatives, various acid halides and various alkylsulfonylhalides, and in the same manner as Examples 14, 15, 33, and 34,the compounds shown in Table 10 below are produced. TABLE 10

yield Cpd. No. R¹ (%) mp (° C.) 1 HOCH₂CH₂CONH 38 207-209(hydrochloride) 2 MeONHCONH 50 154-158 (hydrochloride) 3

68 153-156 (hydrochloride) 4

38 155(dc.) (hydrochloride) 5

44 162-164 (hydrochloride) 6

100  92-107 (hydrochloride) 7

90 155-163 (hydrochloride) 8

75 152-154 (hydrochloride) 9

14 169-173 (hydrochloride) 10

47 201-204 (hydrochloride) 11

36 144-149 (hydrochloride) 12

43 209-211 (hydrochloride) 13 EtOOCNH 44 197-200 (hydrochloride) 14

49 172-175 (hydrochloride) 15

37 202-204 (hydrochloride) 16

64 166-170 (dihydrochloride) 17

67 164-167 (hydrochloride) 18

26 157-162 (hydrochloride) 19

9 144-148 (hydrochloride) 20

70 152-155 (hydrochloride) 21

53 199-204 (hydrochloride) 22

64 177-179 (hydrochloride) 23 CH₂═CHCONH 49 158-161 (hydrochloride) 24

55 190-193 (hydrochloride) 25

50 165-168 (hydrochloride) 26

40 159-160 (hydrochloride) 27

58 157-158 (hydrochloride) 28 EtCONH 61 158-166 (hydrochloride) 29EtSO₂NH 27 155-160 (hydrochloride) 30 Me(HO)CHCH₂NH 24  89-91(free base)31 CF₃CONH 83 172-174(free base) 32

74 147-149(free base) 33 MeCH₂CH₂NH 18  66-68(free base)

EXAMPLE 36 Preparation of8-(2,6-difluorobenzyl)-5,8-dihydro-2-(4-hydroxyphenyl)-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester

[0407]

[0408] To a solution of the compound No. 23 obtained in Example 10 (3.1g, 5.16 mmol) in dichloromethane (30 ml) is added a solution of sodiumethoxide (0.35 g, 5.16 mmol) in ethanol (20 ml) with ice-cooling. Themixture is stirred at this temperature for 1 hour and neutralized with1N hydrochloric acid, successively concentrated under reduced pressureto give the residue, which is partitioned between chloroform (50 ml) andwater (50 ml). The aqueous layer is extracted with chloroform (20 ml).The combined organic layer is dried over Na₂SO₄ and concentrated underreduced pressure to give a yellow solid, which is chromatographed onsilica gel to afford a white amorphous (1.41 g, 49t).

[0409]¹H-NMR (CDCl₃) δ: 1.36(3H, t), 2.20(3H, s), 3.68(2H, s),4.35-4.42(4H,m), 5.50(2H, s), 6.90(2H, d), 6.99(2H, t), 7.14-7.55(5H,m), 7.89(2H, d), 8.39(1H, s).

[0410] FAB-MS m/e 559.3 (MH⁺).

[0411] Anal. Calcd for C₃₁H₂₈N₄O₄F₂.0.5H₂O: C, 65.60 ; H, 5.15; N, 9.87.Found: C, 65.49; H, 5.22; N, 9.77.

Experimental Example 1

[0412] (1) Preparation of ¹²⁵I-leuprorelin

[0413] To a tube containing 10 μl of a 3×10⁻⁴ M aqueous solution ofleuprorelin and 10 μl of 0.01 mg/ml lactoperoxidase, 10 μl (37 MBq) of asolution of Na¹²⁵I was added. After stirring, 10 μl of 0.001% H₂O₂ wasadded, and a reaction was carried out at about 15 to 25° C. for 20minutes. By adding 700 μl of a 0.05% TFA (trifluoroacetic acid)solution, the reaction was stopped, followed by purification byreversed-phase HPLC. The HPLC conditions used are shown below.¹²⁵I-leuprorelin was eluted at a retention time of 26 to 27 minutes.Column: TSKgel ODS-80™ (™ indicates a registered trademark; the sameapplies below) CTR (4.6 mm×10 cm)

[0414] Eluents:

[0415] Solvent A (0.05% TFA)

[0416] Solvent B (40% CH3CN-0.05% TFA)

[0417] 0 minute (100% Solvent A)-3 minutes (100%

[0418] Solvent A)-7 minutes (50% Solvent A+50%

[0419] Solvent B)-40 minutes (100% Solvent B)

[0420] Eluting temperature: About 15 to 25° C.

[0421] Elution rate: 1 ml/min

[0422] (2) Preparation of CHO (Chinese Hamster Ovarian) Cell MembraneFraction Containing Human GnRH Receptor

[0423] Human GnRH receptor-expressing CHO cells (10⁹ cells) as preparedby the method described in European Patent Publication No. EP-0678577Awere suspended in phosphate-buffered saline supplemented with 5 mM EDTA(ethylenediaminetetraacetic acid) (PBS-EDTA) and centrifuged at 100×gfor 5 minutes. To the cell pellet, 10 ml of a cell homogenate buffer (10mM NaHCO₃, 5 mM EDTA, pH 7.5) was added, followed by homogenizationusing the Polytron homogenizer. After centrifugation at 400×g for 15minutes, the supernatant was transferred to an ultracentrifugation tubeand centrifuged at 100,000×g for 1 hour to yield a membrane fractionprecipitate. This precipitate was suspended in 2 ml of an assay buffer(25 mM Tris-HCl, 1 mM EDTA, 0.1% BSA (bovine serum albumin), 0.25 mMPMSF (phenylmethanesulfonyl fluoride), 1 μg/ml pepstatin, 20 μg/mlleupeptine, 100 μg/ml phosphoramidone, 0.03% sodium azide, pH 7.5) andcentrifuged at 100,000×g for 1 hour. The membrane fraction recovered asa precipitate was again suspended in 20 ml of the assay buffer,dispensed, and stored at −80° C. before use upon thawing.

[0424] (3) Determination of ¹²⁵1-leuprorelin Binding Inhibition Rate

[0425] The human membrane fraction prepared in paragraph (2) above wasdiluted with the assay buffer to yield a 200 μg/ml dilution, which wasthen dispensed at 188 μl per tube. To each tube, 2 μl of a solution of 2mM compound in 60% DMSO (dimethyl sulfoxide) and 10 μl of 38 nM¹²⁵I-leuprorelin were added simultaneously. To determine maximum bindingquantity, a reaction mixture of 2 μl of 60% DMSO and 10 μl of 38 nM¹²⁵I-leuprorelin was prepared. To determine non-specific binding amount,a reaction mixture of 2 μl of 100 μM leuprorelin in solution in 60% DMSOand 10 μl of 38 nM ¹²⁵I-leuprorelin was prepared.

[0426] After a reaction was carried out at 25° C. for 60 minutes, thereaction mixture was aspirated and filtered through apolyethyleneimine-treated Whatman glass filter (GF-F). After thisfiltration, the radioactivity of ¹²⁵I-leuprorelin remaining on thefilter paper was measured, using a γ-counter.

[0427] The binding inhibition rate (%) for the subject compound (PMB)was calculated, using the equation:

PMB=(TB−SB)/(TB−NSB)×100

[0428] TB=maximum bound radioactivity

[0429] SB=radioactivity in presence of subject compound

[0430] NSB=non-specific bound radioactivity

[0431] Inhibitory rates were then obtained for varied concentrations ofthe subject compound, and the subject compound concentration for 50%inhibition of binding (concentration for 50% PMB, IC₅₀ value) wascalculated from a Hill plot.

[0432] The IC₅₀ values of the compounds obtained in Examples above, asobtained by the determination method described above, are shown in Tablebelow. TABLE 11 Example No. IC₅₀ (nM) 15 0.5

Preparation Example 1

[0433] Using the compound produced in Example 10 (Compound 6) (100 mg),165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol and 1mg of magnesium stearate, tablets are produced by a conventional method.

Preparation Example 2

[0434] The compound produced in Example 10 (Compound 6) (5 g) isdissolved in distilled water for injection to make a total volume of 100ml. This solution is aseptically filtered through a 0.22 μm membranefilter (produced by Sumitomo Electric Industries, Ltd. or Sartorius) anddispensed at 2 ml per washed sterile vial, followed by freeze-drying bya conventional method, to yield a 100 mg/vial freeze-dried injectablepreparation.

Preparation Example 3

[0435] Using the compound produced in Example 14 (100 mg), 165 mg oflactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol and 1 mg ofmagnesium stearate, tablets are produced by a conventional method.

Preparation Example 4

[0436] The compound produced in Example 14 (5 g) is dissolved indistilled water for injection to make a total volume of 100 ml. Thissolution is aseptically filtered through a 0.22 tm membrane filter(produced by Sumitomo Electric Industries, Ltd. or Sartorius) anddispensed at 2 ml per washed sterile vial, followed by freeze-drying bya conventional method, to yield a 100 mg/vial freeze-dried injectablepreparation.

Preparation Example 5

[0437] Using the compound produced in Example 15 (100 mg), 165 mg oflactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol and 1 mg ofmagnesium stearate, tablets are produced by a conventional method.Preparation Example 6 (1) Compound produced in Example 10 (Compound 6) 5g (2) Lactose/crystalline cellulose (particles) 330 g (3) D-mannitol 29g (4) Low-substitutional hydroxypropyl cellulose 20 g (5) Talc 25 g (6)Hydroxypropyl cellulose 50 g (7) Aspartame 3 g (8) Dipotassiumglycyrrhizinate 3 g (9) Hydroxypropylmethyl cellulose 2910 30 g (10)Titanium oxide 3.5 g (11) Yellow iron sesquioxide 0.5 g (12) Lightsilicic anhydride 1 g

[0438] Components (1), (3), (4), (5), (6), (7) and (8) are suspended ordissolved in purified water and coated on the core particles (2) toyield base fine subtilae, which are then further coated with components(9) through (11) to yield coated fine subtilae, which are then mixedwith component (12) to yield 500 g of 1% fine subtilae of the compoundobtained in Example 10 (compound 6). These subtilae are divided to 500mg folded subtilae.

[0439] Industrial Applicability

[0440] The compound of the present invention possesses excellentgonadotropin-releasing hormone antagonizing activity. It is also good inoral absorbability and excellent in stability and pharmacokinetics. Withlow toxicity, it is also excellent in safety.

[0441] The compound of the present invention can therefore be used as aprophylactic or therapeutic agent for hormone-dependent diseases etc.Specifically, it is effective as a prophylactic or therapeutic agent forsex hormone-dependent cancers (e.g., prostatic cancer, uterine cancer,breast cancer, pituitary tumor), prostatic hypertrophy, hysteromyoma,endometriosis, precocious puberty, amenorrhea syndrome, multilocularovary syndrome, pimples etc, or as a pregnancy regulator (e.g.,contraceptive), infertility remedy or menstruation regulator. It is alsoeffective as an animal estrous regulator, food meat quality improvingagent or animal growth regulator in the field of animal husbandry, andas a fish spawning promoter in the field of fishery.

1. A compound of the formula (I):

wherein one of A and D represents a nitrogen atom and the otherrepresents a carbon atom, or both represent a nitrogen atom; Brepresents a nitrogen atom or a carbon atom; m represents an integerfrom 0 to 3; R¹, R² and R³ each represents (i) hydrogen or (ii) a groupbound via a carbon atom, a nitrogen atom, an oxygen atom or a sulfuratom; R⁴ represents a group bound via a carbon atom; R⁵ represents (i)hydrogen, (ii) halogen or (iii) a group bound via a carbon atom or anoxygen atom; R⁶ represents hydrogen or a group bound via a carbon atom;R⁷ represents a homocyclic group which may be substituted or aheterocyclic group which may be substituted; and each dotted linerepresents a single bond or a double bond, or a salt thereof:
 2. Acompound of claim 1 or a salt thereof, wherein R¹, R² and R³ each is (1)hydrogen, (2) a hydrocarbon group which may be substituted, (3) an acylgroup which may be substituted, (4) a heterocyclic group having a bondin a carbon atom thereof which may be substituted, (5) a group of theformula: —COOR²¹ wherein R²¹ is hydrogen, a hydrocarbon group which maybe substituted or a heterocyclic group which may be substituted, (6) agroup of the formula: —CO—NR¹⁵R¹⁶ wherein R¹⁵ is hydrogen, a hydrocarbongroup which may be substituted or a C₁₋₁₀ alkoxy group; and R¹⁶ ishydrogen or a hydrocarbon group which may be substituted; or R¹⁵ and R¹⁶form, taken together with the adjacent nitrogen atom, a cyclic aminogroup which may be substituted, (7) a cyano group, (8) a nitro group,(9) a group of the formula: —NR⁸R⁹ wherein R⁸ is (i) hydrogen, (ii) ahydrocarbon group which may be substituted, (iii) an acyl group whichmay be substituted, (iv) a group of the formula: —O—R¹³ wherein R¹³ ishydrogen, a C₁₋₁₀ hydrocarbon group which may be substituted, a C₁₋₂₀acyl group which may be substituted, a C₁₋₂₀ alkylsulfonyl group whichmay be substituted, a C₆₋₁₄ arylsulfonyl group which may be substitutedor a heterocyclic group which may be substituted, (v) a heterocyclicgroup which may be substituted or (vi) a group of the formula:—S(O)t-R¹² wherein t is an integer from 0 to 2, and R¹² is hydrogen or aC₁₋₁₀ hydrocarbon group which may be substituted; R⁹ is hydrogen, ahydrocarbon group which may be substituted or an acyl group which may besubstituted; or R⁸ and R⁹ form, taken together with the adjacentnitrogen atom, a cyclic amino group which may be substituted, (10) agroup of the formula: —O—R¹³ wherein R¹³ is as defined above, or (11) agroup of the formula: —S(O)t-R¹⁴ wherein t is an integer from 0 to 2,and R¹⁴ is hydrogen, a hydrocarbon group which may be substituted or aheterocyclic group which may be substituted; R⁴ is (1) a hydrocarbongroup which may be substituted, (2) an acyl group which may besubstituted, (3) a heterocyclic group having a bond in a carbon atomthereof which may be substituted, (4) a group of the formula: —COOR²¹wherein R²¹ is as defined above, (5) a group of the formula: —CO—NR¹⁵R¹⁶wherein each symbol is as defined above, or (6) a cyano group; R⁵ is (1)hydrogen, (2) halogen, (3) a hydrocarbon group which may be substituted,(4) an acyl group which may be substituted, (5) a heterocyclic grouphaving a bond in a carbon atom thereof which may be substituted, (6) agroup of the formula: —COOR²¹ wherein R²¹ is as defined above, (7) agroup of the formula: —CO—NR¹⁵R¹⁶ wherein each symbol is as definedabove, (8) a cyano group, or (9) a group of the formula: —O—R¹³ whereinR¹³ is as defined above; R⁶ is (1) hydrogen, (2) a hydrocarbon groupwhich may be substituted, (3) an acyl group which may be substituted,(4) a heterocyclic group having a bond in a carbon atom thereof whichmay be substituted, (5) a group of the formula: —COOR²¹ wherein R²¹ isas defined above, (6) a group of the formula: —CO—NR¹⁵R¹⁶ wherein eachsymbol is as defined above, or (7) a cyano group; R⁷ is (i) a C₆₋₁₀ arylor C₃₋₇ cycloalkyl group, each of which may be substituted by 1 to 6substituents selected from the group consisting of (1) C₁₋₁₅ alkyl whichmay be substituted by 1 to 3 halogen, (2) C₃₋₁₀ cycloalkyl, (3) C₂₋₁₀alkenyl, (4) C₂₋₁₀ alkynyl, (5) C₃₋₁₀ cycloalkenyl, (6) C₆₋₁₀ aryl, (7)C₇₋₂₀ aralkyl, (8) nitro, (9) hydroxy, (10) mercapto, (11) oxo, (12)thioxo, (13) cyano, (14) carbamoyl, (15) carboxyl, (16) C₁₋₆alkoxy-carbonyl, (17) sulfo, (18) halogen, (19) C₁₋₆ alkoxy, (20) C₆₋₁₀aryloxy, (21) C₁₋₆ alkanoyloxy, (22) C₁₋₆ alkylthio, (23) C₆₋₁₀arylthio, (24) C₁₋₆ alkylsulfinyl, (25) C₆₋₁₀ arylsulfinyl, (26) C₁₋₆alkylsulfonyl, (27) C₆₋₁₀ arylsulfonyl, (28) amino, (29) C₁₋₆alkanoylamino, (30) mono- or di-C₁₋₄ alkylamino, (31) C₃₋₈cycloalkylamino, (32) C₆₋₁₀ arylamino, (33) C₁₋₆ alkanoyl, (34) C₆₋₁₀aryl-carbonyl and (35) 5- to 6-membered heterocyclic group, or (ii) aheterocyclic group which may be substituted, in which “hydrocarbongroup” is a C₁₋₂₀ hydrocarbon group selected from C₁₋₁₅ alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C3-10 cycloalkenyl, C₆₋₁₄ aryland C₇₋₂₀ aralkyl; “C₁₋₁₀ hydrocarbon group” is a C₁₋₁₀ alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀ arylor phenyl-C₁₋₄ alkyl group; “acyl group” and “C₁₋₂₀ acyl group” each isformyl, C₁₋₆ alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, C₆₋₁₄ aryl-carbonyl,C₆₋₁₄ aryloxy-carbonyl, C₆₋₁₄ aryl-C₁₋₆ alkyl-carbonyl, C₆₋₁₄ aryl-C₁₋₆alkoxy-carbonyl, C₂₋₄ alkenyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl ortricyclic bridged C₉₋₁₀ hydrocarbon-carbonyl; “heterocyclic group” is(1) a 5- to 8-membered heterocyclic group containing 1 to 4 hetero atomsselected from oxygen atoms, sulfur atoms, nitrogen atoms in addition tocarbon atoms, (2) a bi- or tri-cyclic condensed heterocyclic groupresulting from condensation of 2 or 3 of the above (1) heterocyclicgroup, whether identical or not, or (3) a bi- or tri-cyclic condensedheterocyclic group resulting from condensation of the above (1)heterocyclic group and 1 or 2 benzene rings; “cyclic amino group” is a5- to 7-membered cyclic amino group optionally containing 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, nitrogen atoms inaddition to carbon atoms and a nitrogen atom; “substituent(s)” for the“hydrocarbon group which may be substituted”, the “C₁₋₁₀ hydrocarbongroup which may be substituted”, the “acyl group which may besubstituted”, “C₁₋₂₀ acyl group which may be substituted”, the “C₁₋₂₀alkylsulfonyl group which may be substituted” or the “C₆₋₁₄ arylsulfonylgroup which may be substituted” is selected from 1 to 6 of (1) halogen,(2) nitro, (3) nitroso, (4) cyano, (5)(i) C₁₋₆ alkyl which may besubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkoxy, C₁₋₃ alkylthio,hydroxy-C₁₋₃ alkoxy, C₁₋₆ alkyl-carbonyl, carboxy, carbamoyl, C₁₋₆alkyl-carbamoyl, 5- to 8-membered heterocyclic group and halogen, (ii)C₁₋₄ alkanoyl or C₂₋₄ alkenoyl, (iii) C₆₋₁₄ aryl-C₁₋₆ alkyl which may besubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, C₁₋₃ alkoxy and C₁₋₄ alkyl, (iv) C₆₋₁₄ aryl which may besubstituted by 1 to 3 halogen, (v) C₂₋₆ alkenyl, (vi) C₃₋₇ cycloalkyl,(vii) C₁₋₃ alkoxy-carbonyl, (viii) mono- or di-C₁₋₆ alkyl amino, (ix)C₂₋₆ alkenyl amino, (x) C₁₋₃ alkoxy-carbonyl, (xi) formyl or C₁₋₆alkyl-carbonyl, or (xii) hydroxy which may be substituted by C₃₋₆cycloalkyloxy-carbonyl, (6) a group of the formula: —S(O)t-R¹⁷ wherein tis an integer from 0 to 2, and R¹⁷ is (i) hydrogen or (ii) a C₁₋₆ alkyl,C₆₋₁₄ aryl or C₇₋₂₀ aralkyl group which may be substituted by 1 to 3substituents selected from the group consisting of halogen, nitro,cyano, hydroxy, oxo, thioxo, carboxy, cyano-C₆₋₁₄ aryl andhalogeno-C₆₋₁₄ aryl, (7) a group of the formula: —NR¹⁸R¹⁹ wherein R¹⁸and R¹⁹ each is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylamino-C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, phenyl, phenyl-C₁₋₆ alkyl, C₁₋₆alkanoyl, C₃₋₆ alkenoyl, C₄₋₇ cycloalkyl-carbonyl, phenyl-C₁₋₆alkyl-carbonyl, C₁₋₆ alkoxy-carbonyl, phenyl-C₁₋₆ alkoxy-carbonyl or 5-to 8-membered heterocyclic group, (8) a group of the formula: —CO—R²⁰wherein R²⁰ is (i) hydrogen, (ii) hydroxy, (iii) C₁₋₁₀ alkyl or (iv)C₁₋₆ alkoxy which may be substituted by C₆₋₁₄ aryl which may besubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and nitro, (v) C₃₋₆ cycloalkyl, (vi) C₆₋₁₄ aryl, (vii) C₆₋₁₄aryloxy, (viii) C₇₋₂₀ aralkyl, (ix) a group of the formula: —NR¹⁰R¹¹wherein R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a group of theformula: —O—R¹³ wherein R¹³ is as defined above, a heterocyclic groupwhich may be substituted or a group of the formula: —S(O)t-R¹² whereineach symbol is as defined above; and R¹¹ is hydrogen or a C₁₋₁₀hydrocarbon group; or R¹⁰ and R¹¹ form, taken together with the adjacentnitrogen atom, a cyclic amino group which may be substituted, or (x) 5-to 8-membered heterocyclic group, (9) 5- to 8-membered heterocyclicgroup which may be substituted by 1 to 3 substituents selected form thegroup consisting of hydroxy, amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄alkoxy, halogen, nitro and C₁₋₆ alkyl, (10) sulfo, (11) C₆₋₁₄ aryl whichmay be substituted by 1 to 3 substituents selected form the groupconsisting of hydroxy, amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy,halogen, nitro and C₁₋₆ alkyl, (12) C₃₋₇ cycloalkyl which may besubstituted by 1 to 3 substituents selected form the group consisting ofhydroxy, amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitroand C₁₋₆ alkyl, (13) C₁₋₆ alkylenedioxy, (14) oxo, (15) thioxo, (16)C₂₋₄ alkynyl which may be substituted by 1 to 3 substituents selectedform the group consisting of hydroxy, amino, mono- or di-C₁₋₄alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (17) C₃₋₁₀cycloalkyl which may be substituted by 1 to 3 substituents selected formthe group consisting of hydroxy, amino, mono- or di-C₁₋₄ alkylamino,C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl, (18) C₂₋₁₀ alkenyl which maybe substituted by 1 to 3 substituents selected form the group consistingof hydroxy, amino, mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen,nitro and C₁₋₆ alkyl, (19) C₇₋₂₀ aralkyl which may be substituted by 1to 3 substituents selected form the group consisting of hydroxy, amino,mono- or di-C₁₋₄ alkylamino, C₁₋₄ alkoxy, halogen, nitro and C₁₋₆ alkyl,(20) amidino and (21) azido; “substituent(s)” for the “heterocyclicgroup which may be substituted” or the “heterocyclic group having a bondin a carbon atom thereof which may be substituted” is selected from 1 to6 of (1) C₁₋₆ alkyl, (2) C₂₋₆ alkenyl, (3) C₂₋₆ alkynyl, (4) C₃₋₆cycloalkyl, (5) C₅₋₇ cycloalkenyl, (6) C₆₋₁₀ aryl-C₁₋₅ alkyl, (7) C₆₋₁₄aryl, (8) C₁₋₆ alkoxy, (9) C₆₋₁₄ aryloxy, (10) C₁₋₆ alkanoyl, (11) C₆₋₁₄aryl-carbonyl, (12) C₁₋₆ alkanoyloxy, (13) C₆₋₁₄ aryl-carbonyloxy, (14)carboxyl, (15) C₁₋₆ alkoxy-carbonyl, (16) carbamoyl, (17) N-mono-C₁₋₄alkylcarbamoyl, (18) N,N-di-C₁₋₄ alkylcarbamoyl, (19) 3- to 6-memberedcyclic aminocarbonyl, (20) halogen, (21) mono-, di- or tri-halogeno-C₁₋₄alkyl, (22) oxo, (23) amidino, (24) imino, (25) amino, (26) mono- ordi-C₁₋₄ alkylamino, (27) 3- to 6-membered cyclic amino, (28) C₁₋₆alkanoylamino, (29) benzamido, (30) carbamoylamino, (31) N—C₁₋₄alkylcarbamoylamino, (32) N,N-di-C₁₋₄ alkylcarbamoylamino, (33) C₁₋₃alkylenedioxy, (34) —B(OH)₂, (35) hydroxy, (36) epoxy, (37) nitro, (38)cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43)sulfamoyl, (44) C₁₋₆ alkylsulfamoyl, (45) di-C₁₋₆ alkylsulfamoyl, (46)C₁₋₆ alkylthio, (47) phenylthio, (48) C₁₋₆ alkylsulfinyl, (49)phenylsulfinyl, (50) C₁₋₆ alkylsulfonyl and (51) phenylsulfonyl; and“substituent(s)” for the “cyclic amino group which may be substituted”is selected from 1 to 3 of C₁₋₆ alkyl, C₆₋₁₄ aryl, phenyl-C₁₋₄ alkyl,benzhydryl, C₁₋₆ alkyl-carbonyl, C₆₋₁₄ aryl-carbonyl and C₁₋₆alkoxy-carbonyl.
 3. A compound of claim 1 or a salt thereof, wherein Ais a nitrogen atom.
 4. A compound of claim 1 or a salt thereof, whereinB is a nitrogen atom.
 5. A compound of claim 1 or a salt thereof,wherein D is a nitrogen atom.
 6. A compound of claim 1 or a saltthereof, wherein m is
 1. 7. A compound of claim 1 or a salt thereof,wherein R¹ is (1) a C₁₋₁₅ alkyl group which may be substituted, (2) aC₃₋₁₀ cycloalkyl group which may be substituted, (3) a C₂₋₁₀ alkenylgroup which may be substituted, (4) a C₂₋₁₀ alkynyl group which may besubstituted, (5) a C₃₋₁₀ cycloalkenyl group which may be substituted,(6) a C₆₋₁₄ aryl group which may be substituted, (7) a C₇₋₂₀ aralkylgroup which may be substituted, (8) a C₁₋₂₀ acyl group which may besubstituted, (9) a nitro group, (10) a group of the formula: —NR¹⁰R¹¹wherein R¹⁰ is hydrogen, a C₁₋₁₀ hydrocarbon group which may besubstituted, a C₁₋₂₀ acyl group which may be substituted, a hydroxygroup which may be substituted, a heterocyclic group which may besubstituted or a group of the formula: —S(O)t-R¹² wherein t is aninteger from 0 to 2, and R¹² is hydrogen or a C₁₋₁₀ hydrocarbon groupwhich may be substituted; R¹¹ is hydrogen or a C₁₋₁₀ hydrocarbon group;or R¹⁰ and R¹¹ form, taken together with the adjacent nitrogen atom, acyclic amino group which may be substituted, or (11) a group of theformula: —O—R¹³ wherein R¹³ is hydrogen, a C₁₋₁₀ hydrocarbon group whichmay be substituted, a C₁₋₂₀ acyl group which may be substituted, a C₁₋₂₀alkylsulfonyl group which may be substituted, a C₆₋₁₄ arylsulfonyl groupwhich may be substituted, or a heterocyclic group which may besubstituted; and R² and R³ each is hydrogen.
 8. A compound of claim 1 ora salt thereof, wherein R² and R³ each is hydrogen.
 9. A compound ofclaim 8 or a salt thereof, wherein the position of R¹ is para-position.10. A compound of claim 1 or a salt thereof, wherein R¹ is (1) an aminogroup which may be substituted by (i) carbamoyl which may be substitutedby C₁₋₆ alkyl or C₁₋₆ alkoxy, or (ii) C₁₋₆ alkyl-carbonyl, or (2) a C₁₋₆alkoxy group which may be substituted by C₃₋₆ cycloalkyl.
 11. A compoundof claim 1 or a salt thereof, wherein R⁴ is a C₁₋₁₅ alkyl group whichmay be substituted, a C₃₋₁₀ cycloalkyl group which may be substituted, aC₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀ alkynyl groupwhich may be substituted, a C₃₋₁₀ cycloalkenyl group which may besubstituted, a C₆₋₁₄ aryl group which may be substituted or a C₇₋₂₀aralkyl group which may be substituted.
 12. A compound of claim 1 or asalt thereof, wherein R⁴ is a C₁₋₆ alkyl group which may be substituted.13. A compound of claim 1 or a salt thereof, wherein R⁴ is a C₁₋₆ allylgroup which may be substituted by halogen, hydroxy which may besubstituted or amino which may be substituted.
 14. A compound of claim 1or a salt thereof, wherein R⁴ is a group of the formula: —(CH₂)n-NR¹⁰R¹¹wherein n is an integer from 1 to 3; R¹⁰ is hydrogen, a C₁₋₁₀hydrocarbon group which may be substituted, a C₁₋₂₀ acyl group which maybe substituted, a hydroxy group which may be substituted, a heterocyclicgroup which may be substituted, or a group of the formula: —S(O)t-R¹²wherein t is an integer from 0 to 2, and R¹² is hydrogen or a C₁₋₁₀hydrocarbon group which may be substituted; and R¹¹ is hydrogen or aC₁₋₁₀ hydrocarbon group; or R¹⁰ and R¹¹ form, taken together with theadjacent nitrogen atom, a cyclic amino group which may be substituted.15. A compound of claim 1 or a salt thereof, wherein R⁴ is a N—C₁₋₆alkyl-N-benzylaminomethyl group.
 16. A compound of claim 1 or a saltthereof, wherein R⁵ is hydrogen, halogen, a C₁₋₁₅ alkyl group which maybe substituted, a C₃₋₁₀ cycloalkyl group which may be substituted, aC₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀ alkynyl groupwhich may be substituted, a C₃₋₁₀ cycloalkenyl group which may besubstituted, a C₆₋₁₄ aryl group which may be substituted, a C₇₋₂₀aralkyl group which may be substituted, a C₁₋₂₀ acyl group which may besubstituted, a carboxy group which may be esterified or amidated, or agroup of the formula: —OR¹³ wherein R¹³ is hydrogen or a C₁₋₁₅ alkylgroup which may be substituted, a C₃₋₁₀ cycloalkyl group which may besubstituted, a C₂₋₁₀ alkenyl group which may be substituted, a C₂₋₁₀alkynyl group which may be substituted, a C₃₋₁₀ cycloalkenyl group whichmay be substituted, a C₆₋₁₄ aryl group which may be substituted, a C₇₋₂₀aralkyl group which may be substituted, a C₁₋₂₀ acyl group which may besubstituted, a C₁₋₂₀ alkysulfonyl group which may be substituted, aC₆₋₁₄ arylsulfonyl group which may be substituted or a heterocyclicgroup which may be substituted.
 17. A compound of claim 1 or a saltthereof, wherein R⁵ is (1) a C₁₋₆ alkoxy-carbonyl group, (2) a C₆₋₁₀aryl group which may be substituted by halogen or C₁₋₆ alkoxy, or (3) aphenyl-C₁₋₃ alkyl group.
 18. A compound of claim 1 or a salt thereof,wherein R⁶ is hydrogen, a C₁₋₁₅ alkyl group which may be substituted, aC₃₋₁₀ cycloalkyl group which may be substituted, a C₂₋₁₀ alkenyl groupwhich may be substituted, a C₂₋₁₀ alkynyl group which may besubstituted, a C₃₋₁₀ cycloalkenyl group which may be substituted, aC₆₋₁₄ aryl group which may be substituted or a C₇₋₂₀ aralkyl group whichmay be substituted.
 19. A compound of claim 1 or a salt thereof, whereinR⁶ is hydrogen or a C₁₋₆ alkyl group. R⁵ is (1) a C₁₋₆ alkoxy-carbonylgroup, (2) a C₆₋₁₀ aryl group which may be substituted by halogen orC₁₋₆ alkoxy, or (3) a phenyl-C₁₋₃ alkyl group; and R⁶ is hydrogen.
 27. Acompound of claim 25 or a salt thereof, wherein R¹ is (1) a nitro group,(2) an amino group which may be substituted by 1 or 2 substituentsselected from the group consisting of (i) C₁₋₆ alkyl which may besubstituted by hydroxy, (ii) C₁₋₆ alkyl-carbonyl which may besubstituted by hydroxy, halogen or thienyl, (iii) C₆₋₁₀ aryl-carbonylwhich may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, (iv)C₃₋₆ cycloalkyl-carbonyl, (v) C₂₋₄ alkenyl-carbonyl, (vi) C₁₋₆alkoxy-carbonyl, (vii) C₁₋₆ alkylamino-carbonyl, (viii) C₁₋₆alkoxyamino-carbonyl, (ix) phenylaminocarbonyl, (x) anisoxazolylcarbonyl, thienylcarbonyl, thiazolylcarbonyl,pyrazolylcarbonyl or furylcarbonyl group which may be substituted by 1or 2 substituents selected from the group consisting of C₁₋₆ alkyl,nitro and C₁₋₆ alkoxy, (xi) pyridylcarbonyl, (xii) C₁₋₆ alkylsulfonyl,(xiii) thienylsulfonyl and (xiv) phenylsulfonyl which may be substitutedby C₁₋₆ alkyl, (3) a pyrrolyl group or (4) a hydroxy group which may besubstituted by C₁₋₆ alkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl or C₁₋₆alkyl-carbonyl; R⁴ is a C₁₋₆ alkyl group which may be substituted by 1or 2 substituents selected from the group consisting of (1) halogen, (2)hydroxy and (3) amino which may be substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆ alkyl, phenyl-C₁₋₃ alkyl anddi-C₁₋₆ alkylamino-C₁₋₃ alkyl; R⁵ is (1) halogen, (2) a phenyl groupwhich may be substituted by halogen or C₁₋₆ alkyl, or (3) a carbonylgroup substituted by (i) C₁₋₆ alkyl, (ii) amino substituted by C₁₋₆alkyl and C₁₋₆ alkoxy or (iii) C₁₋₆ alkoxy; and R⁶ is hydrogen or a C₁₋₃alkyl group. 28.8-(2,6-Difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(methoxyaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester, or salts thereof.
 29. A process for producing acompound of claim 23 or a salt thereof, which comprises reacting acompound of the formula (iv): wherein each symbol is as defined in claim23, or a salt thereof, with a compound of the formula: X²—(CH₂)m-R⁷wherein X² is a leaving group; and the other symbols are as defined inclaim 23, or a salt thereof.
 30. A pharmaceutical composition whichcomprises a compound of claim 1 or a salt thereof.
 31. A composition ofclaim 30 which is a gonadotropin-releasing hormone antagonist.
 32. Acomposition of claim 30 for preventing and/or treating a sex hormonedependent disease.
 33. A composition of claim 30 for preventing and/ortreating a sex hormone dependent cancer.
 34. A composition of claim 30for preventing and/or treating prostatic cancer, uterine cancer orbreast cancer.
 35. A composition of claim 30 for preventing and/ortreating prostatic hypertrophy, endometriosis, hysteromyoma orprecocious puberty.
 36. A composition of claim 30 which is a pregnancyregulator.
 37. A composition of claim 30 which is a menstruation cycleregulator.
 38. A method for antagonizing gonadotropin-releasing hormonein a mammal in need thereof which comprises administering to said mammalan effective amount of a compound of claim 1 or a salt thereof with apharmaceutically acceptable excipient, carrier or diluent.
 39. Use of acompound of claim 1 or a salt thereof for manufacturing a pharmaceuticalcomposition for antagonizing gonadotropin-releasing hormone.